Cells

2024

Jump to: 2023, 2022, 2021, 2020

14 pages, 1267 KiB

Open AccessArticle

Sensing of an HIV-1–Derived Single-Stranded RNA-Oligonucleotide Induces Arginase 1-Mediated Tolerance

by Chiara Suvieri, Giada Mondanelli, Ciriana Orabona, Maria Teresa Pallotta, Eleonora Panfili, Sofia Rossini, Claudia Volpi and Maria Laura Belladonna

Cells 2024, 13(13), 1088; https://doi.org/10.3390/cells13131088 - 23 Jun 2024

Viewed by 933

Abstract

Small synthetic oligodeoxynucleotides (ODNs) can mimic microbial nucleic acids by interacting with receptor systems and promoting immunostimulatory activities. Nevertheless, some ODNs can act differently on the plasmacytoid dendritic cell (pDC) subset, shaping their immunoregulatory properties and rendering them suitable immunotherapeutic tools in several [...] Read more.

Small synthetic oligodeoxynucleotides (ODNs) can mimic microbial nucleic acids by interacting with receptor systems and promoting immunostimulatory activities. Nevertheless, some ODNs can act differently on the plasmacytoid dendritic cell (pDC) subset, shaping their immunoregulatory properties and rendering them suitable immunotherapeutic tools in several clinical settings for treating overwhelming immune responses. We designed HIV–1–derived, DNA- and RNA-based oligonucleotides (gag, pol, and U5 regions) and assessed their activity in conferring a tolerogenic phenotype to pDCs in skin test experiments. RNA-but not DNA-oligonucleotides are capable of inducing tolerogenic features in pDCs. Interestingly, sensing the HIV–1–derived single-stranded RNA-gag oligonucleotide (RNA-gag) requires both TLR3 and TLR7 and the engagement of the TRIF adaptor molecule. Moreover, the induction of a suppressive phenotype in pDCs by RNA-gag is contingent upon the induction and activation of the immunosuppressive enzyme Arginase 1. Thus, our data suggest that sensing of the synthetic RNA-gag oligonucleotide in pDCs can induce a suppressive phenotype in pDCs, a property rendering RNA-gag a potential tool for therapeutic strategies in allergies and autoimmune diseases. Full article

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17 pages, 2637 KiB

Open AccessArticle

ScRNA-Seq Analyses Define the Role of GATA3 in iNKT Cell Effector Lineage Differentiation

by Tzong-Shyuan Tai, Huang-Yu Yang, Wan-Chu Chuang, Yu-Wen Huang, I-Cheng Ho, Ching-Chung Tsai and Ya-Ting Chuang

Cells 2024, 13(12), 1073; https://doi.org/10.3390/cells13121073 - 20 Jun 2024

Viewed by 1170

Abstract

While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads [...] Read more.

While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads to the absence of iNKT2 and iNKT17 cell subsets, as well as an altered distribution of iNKT1 cells. Thymic iNKT cells lacking GATA-3 exhibited diminished expression of PLZF and T-bet, key transcription factors involved in iNKT cell differentiation, and reduced production of Th2, Th17, and cytotoxic effector molecules. Single-cell transcriptomics revealed a comprehensive absence of iNKT17 cells, a substantial reduction in iNKT2 cells, and an increase in iNKT1 cells in GATA-3-deficient thymi. Differential expression analysis highlighted the regulatory role of GATA-3 in T cell activation signaling and altered expression of genes critical for iNKT cell differentiation, such as Icos, Cd127, Eomes, and Zbtb16. Notably, restoration of Icos, but not Cd127, expression could rescue iNKT cell development in GATA-3-deficient mice. In conclusion, our study demonstrates the pivotal role of GATA-3 in orchestrating iNKT cell effector lineage differentiation through the regulation of T cell activation pathways and Icos expression, providing insights into the molecular mechanisms governing iNKT cell development and function. Full article

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2023

Jump to: 2024, 2022, 2021, 2020

16 pages, 3187 KiB

Open AccessArticle

Simultaneous Increases in Intracellular Sodium and Tonicity Boost Antimicrobial Activity of Macrophages

by Luka Krampert, Thomas Ossner, Agnes Schröder, Valentin Schatz and Jonathan Jantsch

Cells 2023, 12(24), 2816; https://doi.org/10.3390/cells12242816 - 11 Dec 2023

Cited by 2 | Viewed by 1752

Abstract

Inflamed and infected tissues can display increased local sodium (Na⁺) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a Na⁺/Ca²⁺-exchanger 1 (NCX1)-dependent increase in intracellular Na⁺ levels. This [...] Read more.

Inflamed and infected tissues can display increased local sodium (Na⁺) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a Na⁺/Ca²⁺-exchanger 1 (NCX1)-dependent increase in intracellular Na⁺ levels. This results in augmented osmoprotective signaling and enhanced proinflammatory activation, such as enhanced expression of type 2 nitric oxide synthase and antimicrobial function. In this study, the role of elevated intracellular Na⁺ levels in macrophages was investigated. Therefore, the Na⁺/K⁺-ATPase (NKA) was pharmacologically inhibited with two cardiac glycosides (CGs), ouabain (OUA) and digoxin (DIG), to raise intracellular Na⁺ without increasing extracellular Na⁺ levels. Exposure to HS conditions and treatment with both inhibitors resulted in intracellular Na⁺ accumulation and subsequent phosphorylation of p38/MAPK. The CGs had different effects on intracellular Ca²⁺ and K⁺ compared to HS stimulation. Moreover, the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) was not upregulated on RNA and protein levels upon OUA and DIG treatment. Accordingly, OUA and DIG did not boost nitric oxide (NO) production and showed heterogeneous effects toward eliminating intracellular bacteria. While HS environments cause hypertonic stress and ionic perturbations, cardiac glycosides only induce the latter. Cotreatment of macrophages with OUA and non-ionic osmolyte mannitol (MAN) partially mimicked the HS-boosted antimicrobial macrophage activity. These findings suggest that intracellular Na⁺ accumulation and hypertonic stress are required but not sufficient to mimic boosted macrophage function induced by increased extracellular sodium availability. Full article

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13 pages, 2301 KiB

Open AccessArticle

Double Positive CD4⁺CD8⁺ (DP) T-Cells Display Distinct Exhaustion Phenotype in Chronic Hepatitis C

by Anna Maria Kochanowicz, Sylwia Osuch, Hanna Berak, Aleksandra Kumorek and Kamila Caraballo Cortés

Cells 2023, 12(10), 1446; https://doi.org/10.3390/cells12101446 - 22 May 2023

Cited by 2 | Viewed by 2051

Abstract

In chronic hepatitis C (CHC), characterized by exhaustion of T-cell function, increased frequencies of double-positive (DP) (CD4⁺CD8⁺) cells are present in peripheral blood. We compared the exhaustion phenotype between DP and single positive (SP) T-cells, including HCV-specific cells, and [...] Read more.

In chronic hepatitis C (CHC), characterized by exhaustion of T-cell function, increased frequencies of double-positive (DP) (CD4⁺CD8⁺) cells are present in peripheral blood. We compared the exhaustion phenotype between DP and single positive (SP) T-cells, including HCV-specific cells, and assessed the effect of successful HCV treatment on inhibitory receptors expression. Blood samples from 97 CHC patients were collected before and six months post-treatment. PD-1 (programmed cell death protein 1) and Tim-3 (T-cell immunoglobulin and mucin domain-containing molecule-3) expression was assessed by flow cytometry. DP T-cells displayed significantly higher PD-1 expression, lower Tim-3 expression than CD8⁺ SP T-cells and lower percentages of PD-1⁻Tim-3⁻ cells than CD4⁺ SP T-cells, both before and after treatment. PD-1⁺Tim-3⁺ DP T-cells decreased following treatment. HCV-specific cells were more frequent among DP than SP T-cells, both before and after treatment. HCV-specific DP T-cells were characterized by lower PD-1 expression, higher PD-1 and Tim-3 co-expression, and lower percentages of PD-1⁻Tim-3⁻ cells (both before and after treatment) and higher post-treatment Tim-3 than HCV-specific SP T-cells. Their percentages decreased following treatment, but the exhaustion phenotype remained unchanged. DP T-cells in CHC exhibit a distinct exhaustion phenotype from SP T-cells, and these changes mostly persist following successful treatment. Full article

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2022

Jump to: 2024, 2023, 2021, 2020

22 pages, 3387 KiB

Open AccessReview

Role of Long Noncoding RNAs in the Regulation of Cellular Immune Response and Inflammatory Diseases

by Fen Feng, Peng Jiao, Jinpeng Wang, Yanxia Li, Binwu Bao, Zhuoma Luoreng and Xingping Wang

Cells 2022, 11(22), 3642; https://doi.org/10.3390/cells11223642 - 17 Nov 2022

Cited by 15 | Viewed by 3033

Abstract

Long noncoding RNAs (lncRNAs) are recently discovered genetic regulatory molecules that regulate immune responses and are closely associated with the occurrence and development of various diseases, including inflammation, in humans and animals. Under specific physiological conditions, lncRNA expression varies at the cell or [...] Read more.

Long noncoding RNAs (lncRNAs) are recently discovered genetic regulatory molecules that regulate immune responses and are closely associated with the occurrence and development of various diseases, including inflammation, in humans and animals. Under specific physiological conditions, lncRNA expression varies at the cell or tissue level, and lncRNAs can bind to specific miRNAs, target mRNAs, and target proteins to participate in certain processes, such as cell differentiation and inflammatory responses, via the corresponding signaling pathways. This review article summarizes the regulatory role of lncRNAs in macrophage polarization, dendritic cell differentiation, T cell differentiation, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanism of lncRNAs in acute kidney injury, hepatitis, inflammatory injury of the lung, osteoarthritis, mastitis, and neuroinflammation to provide a reference for the molecular regulatory network as well as the genetic diagnosis and treatment of inflammatory diseases in humans and animals. Full article

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23 pages, 3566 KiB

Open AccessReview

The Role of Inflammatory Mediators in Colorectal Cancer Hepatic Metastasis

by Lavanya Goodla and Xiang Xue

Cells 2022, 11(15), 2313; https://doi.org/10.3390/cells11152313 - 27 Jul 2022

Cited by 22 | Viewed by 3930

Abstract

Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal [...] Read more.

Colorectal cancer (CRC) is the second leading cause of death in cancer patients in the USA, whereas the major cause of CRC deaths is hepatic metastases. The liver is the most common site of metastasis in patients with CRC due to hepatic portal veins receiving blood from the digestive tract. Understanding the cellular and molecular mechanisms of hepatic metastases is of dire need for the development of potent targeted therapeutics. Immuno-signaling molecules including cytokines and chemokines play a pivotal role in hepatic metastases from CRC. This brief review discusses the involvement of three representative cytokines (TNF-α, IL-6 and IL-1β), a lipid molecule PGE2 and two chemokines (CXCL1 and CXCL2) in the process of CRC liver metastases. Full article

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19 pages, 35247 KiB

Open AccessArticle

A Differentiation-Related Gene Prognostic Index Contributes to Prognosis and Immunotherapy Evaluation in Patients with Hepatocellular Carcinoma

by Jingjing Xiao, Tao Liu, Zhenhua Liu, Chuan Xiao, Jun Du, Shi Zuo, Haiyang Li and Huajian Gu

Cells 2022, 11(15), 2302; https://doi.org/10.3390/cells11152302 - 26 Jul 2022

Cited by 8 | Viewed by 2920

Abstract

Hepatocellular carcinoma (HCC) is the most common gastrointestinal tumor with a poor prognosis, which is associated with poor differentiation of tumor cells. However, the potential value of cell differentiation-related molecules in predicting the benefit and prognosis of immune checkpoint inhibitors (ICI) therapy remains [...] Read more.

Hepatocellular carcinoma (HCC) is the most common gastrointestinal tumor with a poor prognosis, which is associated with poor differentiation of tumor cells. However, the potential value of cell differentiation-related molecules in predicting the benefit and prognosis of immune checkpoint inhibitors (ICI) therapy remains unknown. Herein, to investigate the differentiation trajectory of HCC cells and their clinical significance, a differentiation-related gene prognostic index (DRGPI) based on HCC differentiation-related genes (HDRGs) was constructed to elucidate the immune characteristics and therapeutic benefits of ICI in the HCC subgroup defined by DRGPI. Single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data from four HCC samples were integrated for bioinformatics analysis. Then, PON1, ADH4, SQSTM1, HSP90AA1, and STMN1 were screened out to construct a DRGPI. More intriguingly, RT-qPCR validation of the expression of these genes yielded consistent results with the TCGA database. Next, the risk scoring (RS) constructed based on DRGPI suggested that the overall survival (OS) of the DRGPI-high patients was significantly worse than that of the DRGPI-low patients. A nomogram was constructed based on DRGPI-RS and clinical characteristics, which showed strong predictive performance and high accuracy. The comprehensive results indicated that a low DRGPI score was associated with low TP53 mutation rates, high CD8 T cell infiltration, and more benefit from ICI therapy. Homoplastically, the high DRGPI score reflected the opposite results. Taken together, our study highlights the significance of HCC cell differentiation in predicting prognosis, indicating immune characteristics, and understanding the therapeutic benefits of ICI, and suggests that DRGPI is a valuable prognostic biomarker for HCC. Full article

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17 pages, 6030 KiB

Open AccessArticle

The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Dynamical Characterization of Bound and Unbound States

by Josephine Alba and Marco D’Abramo

Cells 2022, 11(4), 668; https://doi.org/10.3390/cells11040668 - 14 Feb 2022

Cited by 4 | Viewed by 3931

Abstract

The machinery involved in cytotoxic T-cell activation requires three main characters: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3 complex, a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has [...] Read more.

The machinery involved in cytotoxic T-cell activation requires three main characters: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3 complex, a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied by means of both experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3 complex) is still missing due to a lack of structural information of the CD3-chains arrangement around the TCR. Very recently, the determination of the TCR:CD3 complex structure by means of Cryo-EM technique has given a chance to build the entire system essential in the activation of T-cells, a fundamental mechanism in the adaptive immune response. Here, we present the first complete model of the pMHC interacting with the TCR:CD3 complex, built in a lipid environment. To describe the conformational behavior associated with the unbound and the bound states, all-atom Molecular Dynamics simulations were performed for the TCR:CD3 complex and for two pMHC:TCR:CD3 complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of this region in the propagation of the signal. Moreover, we found that TCR reduces the flexibility of the MHC I binding groove, confirming our previous results. Full article

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16 pages, 1012 KiB

Open AccessReview

Harnessing Natural Killer Cells in Non-Small Cell Lung Cancer

by Éilis Russell, Melissa J. Conroy and Martin P. Barr

Cells 2022, 11(4), 605; https://doi.org/10.3390/cells11040605 - 10 Feb 2022

Cited by 17 | Viewed by 6374

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. There are two main subtypes: small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of lung cancer diagnoses. Early lung cancer very often has no specific symptoms, [...] Read more.

Lung cancer is the leading cause of cancer-related deaths worldwide. There are two main subtypes: small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC). NSCLC accounts for 85% of lung cancer diagnoses. Early lung cancer very often has no specific symptoms, and many patients present with late stage disease. Despite the various treatments currently available, many patients experience tumor relapse or develop therapeutic resistance, highlighting the need for more effective therapies. The development of immunotherapies has revolutionized the cancer treatment landscape by enhancing the body’s own immune system to fight cancer. Natural killer (NK) cells are crucial anti-tumor immune cells, and their exclusion from the tumor microenvironment is associated with poorer survival. It is well established that NK cell frequencies and functions are impaired in NSCLC; thus, placing NK cell-based immunotherapies as a desirable therapeutic concept for this malignancy. Immunotherapies such as checkpoint inhibitors are transforming outcomes for NSCLC. This review explores the current treatment landscape for NSCLC, the role of NK cells and their dysfunction in the cancer setting, the advancement of NK cell therapies, and their future utility in NSCLC. Full article

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16 pages, 1665 KiB

Open AccessReview

Buffering Adaptive Immunity by Hydrogen Sulfide

by Giulia Pozzi, Giuliana Gobbi, Elena Masselli, Cecilia Carubbi, Valentina Presta, Luca Ambrosini, Marco Vitale and Prisco Mirandola

Cells 2022, 11(3), 325; https://doi.org/10.3390/cells11030325 - 19 Jan 2022

Cited by 18 | Viewed by 4127

Abstract

T cell-mediated adaptive immunity is designed to respond to non-self antigens and pathogens through the activation and proliferation of various T cell populations. T helper 1 (Th1), Th2, Th17 and Treg cells finely orchestrate cellular responses through a plethora of paracrine and autocrine [...] Read more.

T cell-mediated adaptive immunity is designed to respond to non-self antigens and pathogens through the activation and proliferation of various T cell populations. T helper 1 (Th1), Th2, Th17 and Treg cells finely orchestrate cellular responses through a plethora of paracrine and autocrine stimuli that include cytokines, autacoids, and hormones. Hydrogen sulfide (H₂S) is one of these mediators able to induce/inhibit immunological responses, playing a role in inflammatory and autoimmune diseases, neurological disorders, asthma, acute pancreatitis, and sepsis. Both endogenous and exogenous H₂S modulate numerous important cell signaling pathways. In monocytes, polymorphonuclear, and T cells H₂S impacts on activation, survival, proliferation, polarization, adhesion pathways, and modulates cytokine production and sensitivity to chemokines. Here, we offer a comprehensive review on the role of H₂S as a natural buffer able to maintain over time a functional balance between Th1, Th2, Th17 and Treg immunological responses. Full article

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13 pages, 1321 KiB

Open AccessArticle

Raltegravir Inclusion Decreases CD4 T-Cells Intra-Cellular Viral Load and Increases CD4 and CD28 Positive T-Cells in Selected HIV Patients

by Gaurav Kumar, Jacqueline Cottalorda-Dufayard, Rodolphe Garraffo, Francine De Salvador-Guillouët, Eric Cua and Pierre-Marie Roger

Cells 2022, 11(2), 208; https://doi.org/10.3390/cells11020208 - 8 Jan 2022

Cited by 1 | Viewed by 1948

Abstract

Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of [...] Read more.

Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells > 350/mL and <500/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (<10 copies/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients. Full article

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17 pages, 5275 KiB

Open AccessArticle

The Negative Regulative Roles of BdPGRPs in the Imd Signaling Pathway of Bactrocera dorsalis

by Ping Zhang, Zhichao Yao, Shuai Bai and Hongyu Zhang

Cells 2022, 11(1), 152; https://doi.org/10.3390/cells11010152 - 4 Jan 2022

Cited by 5 | Viewed by 2186

Abstract

Peptidoglycan recognition proteins (PGRPs) are key regulators in insects’ immune response, functioning as sensors to detect invading pathogens and as scavengers of peptidoglycan (PGN) to reduce immune overreaction. However, the exact function of PGRPs in Bactrocera dorsalis is still unclear. In this study, [...] Read more.

Peptidoglycan recognition proteins (PGRPs) are key regulators in insects’ immune response, functioning as sensors to detect invading pathogens and as scavengers of peptidoglycan (PGN) to reduce immune overreaction. However, the exact function of PGRPs in Bactrocera dorsalis is still unclear. In this study, we identified and functionally characterized the genes BdPGRP-LB, BdPGRP-SB₁ and BdPGRP-SC₂ in B. dorsalis. The results showed that BdPGRP-LB, BdPGRP-SB₁ and BdPGRP-SC₂ all have an amidase-2 domain, which has been shown to have N-Acetylmuramoyl-l-Alanine amidase activity. The transcriptional levels of BdPGRP-LB and BdPGRP-SC₂ were both high in adult stages and midgut tissues; BdPGRP-SB₁ was found most abundantly expressed in the 2nd instar larvae stage and adult fat body. The expression of BdPGRP-LB and BdPGRP-SB₁ and AMPs were significantly up-regulated after injury infected with Escherichia coli at different time points; however, the expression of BdPGRP-SC₂ was reduced at 9 h, 24 h and 48 h following inoculation with E. coli. By injection of dsRNA, BdPGRP-LB, BdPGRP-SB₁ and BdPGRP-SC₂ were knocked down by RNA-interference. Silencing of BdPGRP-LB, BdPGRP-SB₁ and BdPGRP-SC₂ separately in flies resulted in over-activation of the Imd signaling pathway after bacterial challenge. The survival rate of the ds-PGRPs group was significantly reduced compared with the ds-egfp group after bacterial infection. Taken together, our results demonstrated that three catalytic PGRPs family genes, BdPGRP-LB, BdPGRP-SB₁ and BdPGRP-SC₂, are important negative regulators of the Imd pathway in B. dorsalis. Full article

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2021

Jump to: 2024, 2023, 2022, 2020

19 pages, 2458 KiB

Open AccessArticle

Role of Myeloid Tet Methylcytosine Dioxygenase 2 in Pulmonary and Peritoneal Inflammation Induced by Lipopolysaccharide and Peritonitis Induced by Escherichia coli

by Wanhai Qin, Xanthe Brands, Hisatake Matsumoto, Joe M. Butler, Cornelis van’t Veer, Alex F. de Vos, Joris J. T. H. Roelofs, Brendon P. Scicluna and Tom van der Poll

Cells 2022, 11(1), 82; https://doi.org/10.3390/cells11010082 - 28 Dec 2021

Cited by 8 | Viewed by 2820

Abstract

Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during Escherichia (E.) [...] Read more.

Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during Escherichia (E.) coli induced peritonitis. LPS induced Tet2 expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient (Tet2^fl/flLysM^Cre) mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the Il6 promoter was not altered by Tet2 deficiency. Tet2^fl/flLysM^Cre mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. E. coli induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of Tet2^fl/flLysM^Cre mice after in vivo intraperitoneal infection. Tet2^fl/flLysM^Cre mice displayed enhanced bacterial growth during E. coli peritonitis, which was associated with a reduced capacity of Tet2^fl/flLysM^Cre peritoneal macrophages to inhibit the growth of E. coli in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during E. coli infection. Full article

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17 pages, 691 KiB

Open AccessReview

Myeloid-Derived Suppressor Cells in Prostate Cancer: Present Knowledge and Future Perspectives

by Filippos Koinis, Anastasia Xagara, Evangelia Chantzara, Vassiliki Leontopoulou, Chrissovalantis Aidarinis and Athanasios Kotsakis

Cells 2022, 11(1), 20; https://doi.org/10.3390/cells11010020 - 22 Dec 2021

Cited by 25 | Viewed by 4246

Abstract

Several lines of research are being investigated to better understand mechanisms implicated in response or resistance to immune checkpoint blockade in prostate cancer (PCa). Myeloid-derived suppressor cells (MDSCs) have emerged as a major mediator of immunosuppression in the tumor microenvironment that promotes progression [...] Read more.

Several lines of research are being investigated to better understand mechanisms implicated in response or resistance to immune checkpoint blockade in prostate cancer (PCa). Myeloid-derived suppressor cells (MDSCs) have emerged as a major mediator of immunosuppression in the tumor microenvironment that promotes progression of various tumor types. The main mechanisms underlying MDSC-induced immunosuppression are currently being explored and strategies to enhance anti-tumor immune response via MDSC targeting are being tested. However, the role of MDSCs in PCa remains elusive. In this review, we aim to summarize and present the state-of-the-art knowledge on current methodologies to phenotypically and metabolically characterize MDSCs in PCa. We describe how these characteristics may be linked with MDSC function and may influence the clinical outcomes of patients with PCa. Finally, we briefly discuss emerging strategies being employed to therapeutically target MDSCs and potentiate the long-overdue improvement in the efficacy of immunotherapy in patients with PCa. Full article

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18 pages, 929 KiB

Open AccessReview

New Insights into Epigenetic Regulation of T Cell Differentiation

by Avik Dutta, Harini Venkataganesh and Paul E. Love

Cells 2021, 10(12), 3459; https://doi.org/10.3390/cells10123459 - 8 Dec 2021

Cited by 24 | Viewed by 8461

Abstract

Immature CD4⁻ CD8⁻ thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4⁺ (helper) or CD8⁺ (cytotoxic) T cells. Activation of naïve CD4⁺ and CD8⁺ T cells in the presence of specific cytokines [...] Read more.

Immature CD4⁻ CD8⁻ thymocytes progress through several developmental steps in the thymus, ultimately emerging as mature CD4⁺ (helper) or CD8⁺ (cytotoxic) T cells. Activation of naïve CD4⁺ and CD8⁺ T cells in the presence of specific cytokines results in the induction of transcriptional programs that result in their differentiation into effector or memory cells and in the case of CD4⁺ T cells, the adoption of distinct T-helper fates. Previous studies have shown that histone modification and DNA methylation play important roles in each of these events. More recently, the roles of specific epigenetic regulators in T cell differentiation have been clarified. The identification of the epigenetic modifications and modifiers that control mature T cell differentiation and specification has also provided further insights into how dysregulation of these processes can lead to cancer or autoimmune diseases. In this review, we summarize recent findings that have provided new insights into epigenetic regulation of T cell differentiation in both mice and humans. Full article

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14 pages, 791 KiB

Open AccessReview

The Role of T Cell Immunotherapy in Acute Myeloid Leukemia

by Fang Hao, Christine Sholy, Chen Wang, Min Cao and Xunlei Kang

Cells 2021, 10(12), 3376; https://doi.org/10.3390/cells10123376 - 1 Dec 2021

Cited by 21 | Viewed by 4755

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against [...] Read more.

Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed. Full article

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16 pages, 2905 KiB

Open AccessArticle

Inhibition of O-GlcNAc Transferase Alters the Differentiation and Maturation Process of Human Monocyte Derived Dendritic Cells

by Matjaž Weiss, Marko Anderluh and Martina Gobec

Cells 2021, 10(12), 3312; https://doi.org/10.3390/cells10123312 - 26 Nov 2021

Cited by 11 | Viewed by 3188

Abstract

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells [...] Read more.

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells (moDCs). Our study suggests that inhibition of OGT modulates AKT and MEK/ERK pathways in moDCs. Changes were also observed in the expression levels of relevant surface markers, where reduced expression of CD80 and DC-SIGN, and increased expression of CD14, CD86 and HLA-DR occurred. We also noticed decreased IL-10 and increased IL-6 production, along with diminished endocytotic capacity of the cells, indicating that inhibition of O-GlcNAcylation hampers the transition of monocytes into immature DCs. Furthermore, the inhibition of OGT altered the maturation process of immature moDCs, since a CD14^medDC-SIGN^lowHLA-DR^medCD80^lowCD86^high profile was noticed when OGT inhibitor, OSMI-1, was present. To evaluate DCs ability to influence T cell differentiation and polarization, we co-cultured these cells. Surprisingly, the observed phenotypic changes of mature moDCs generated in the presence of OSMI-1 led to an increased proliferation of allogeneic T cells, while their polarization was not affected. Taken together, we confirm that shifting the O-GlcNAcylation status due to OGT inhibition alters the differentiation and function of moDCs in in vitro conditions. Full article

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17 pages, 2216 KiB

Open AccessArticle

IL-10 mRNA Engineered MSCs Demonstrate Enhanced Anti-Inflammation in an Acute GvHD Model

by Cuiping Zhang, Mina Delawary, Peng Huang, Jennifer A. Korchak, Koji Suda and Abba C. Zubair

Cells 2021, 10(11), 3101; https://doi.org/10.3390/cells10113101 - 10 Nov 2021

Cited by 20 | Viewed by 4792

Abstract

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of [...] Read more.

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD. Full article

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30 pages, 1154 KiB

Open AccessReview

Small Extracellular Vesicles in Transplant Rejection

by Justyna E. Gołębiewska, Anna Wardowska, Monika Pietrowska, Anna Wojakowska and Alicja Dębska-Ślizień

Cells 2021, 10(11), 2989; https://doi.org/10.3390/cells10112989 - 3 Nov 2021

Cited by 20 | Viewed by 4652

Abstract

Small extracellular vesicles (sEV), which are released to body fluids (e.g., serum, urine) by all types of human cells, may stimulate or inhibit the innate and adaptive immune response through multiple mechanisms. Exosomes or sEV have on their surface many key receptors of [...] Read more.

Small extracellular vesicles (sEV), which are released to body fluids (e.g., serum, urine) by all types of human cells, may stimulate or inhibit the innate and adaptive immune response through multiple mechanisms. Exosomes or sEV have on their surface many key receptors of immune response, including major histocompatibility complex (MHC) components, identical to their cellular origin. They also exhibit an ability to carry antigen and target leukocytes either via interaction with cell surface receptors or intracellular delivery of inflammatory mediators, receptors, enzymes, mRNAs, and noncoding RNAs. By the transfer of donor MHC antigens to recipient antigen presenting cells sEV may also contribute to T cell allorecognition and alloresponse. Here, we review the influence of sEV on the development of rejection or tolerance in the setting of solid organ and tissue allotransplantation. We also summarize and discuss potential applications of plasma and urinary sEV as biomarkers in the context of transplantation. We focus on the attempts to use sEV as a noninvasive approach to detecting allograft rejection. Preliminary studies show that both sEV total levels and a set of specific molecules included in their cargo may be an evidence of ongoing allograft rejection. Full article

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11 pages, 732 KiB

Open AccessReview

Harnessing CD8⁺CD28⁻ Regulatory T Cells as a Tool to Treat Autoimmune Disease

by Sabrina Ceeraz, Charlotte R. Thompson, Richard Beatson and Ernest H. Choy

Cells 2021, 10(11), 2973; https://doi.org/10.3390/cells10112973 - 1 Nov 2021

Cited by 12 | Viewed by 3767

Abstract

T regulatory cell therapy presents a novel therapeutic strategy for patients with autoimmune diseases or who are undergoing transplantation. At present, the CD4⁺ Treg population has been extensively characterized, as a result of defined phenotypic and functional readouts. In this review article, [...] Read more.

T regulatory cell therapy presents a novel therapeutic strategy for patients with autoimmune diseases or who are undergoing transplantation. At present, the CD4⁺ Treg population has been extensively characterized, as a result of defined phenotypic and functional readouts. In this review article, we discuss the development and biology of CD8⁺ Tregs and their role in murine and human disease indications. A subset of CD8⁺ Tregs that lack the surface expression of CD28 (CD8⁺CD28⁻ Treg) has proved efficacious in preclinical models. CD8⁺CD28⁻ Tregs are present in healthy individuals, but their impaired functionality in disease renders them less effective in mediating immunosuppression. We primarily focus on harnessing CD8⁺ Treg cell therapy in the clinic to support current treatment for patients with autoimmune or inflammatory conditions. Full article

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16 pages, 4117 KiB

Open AccessArticle

A Microfluidic Flip-Chip Combining Hydrodynamic Trapping and Gravitational Sedimentation for Cell Pairing and Fusion

by Gaurav Pendharkar, Yen-Ta Lu, Chia-Ming Chang, Meng-Ping Lu, Chung-Huan Lu, Chih-Chen Chen and Cheng-Hsien Liu

Cells 2021, 10(11), 2855; https://doi.org/10.3390/cells10112855 - 22 Oct 2021

Cited by 5 | Viewed by 3003

Abstract

Cancer cell–immune cell hybrids and cancer immunotherapy have attracted much attention in recent years. The design of efficient cell pairing and fusion chips for hybridoma generation has been, subsequently, a subject of great interest. Here, we report a three-layered integrated Microfluidic Flip-Chip (MFC) [...] Read more.

Cancer cell–immune cell hybrids and cancer immunotherapy have attracted much attention in recent years. The design of efficient cell pairing and fusion chips for hybridoma generation has been, subsequently, a subject of great interest. Here, we report a three-layered integrated Microfluidic Flip-Chip (MFC) consisting of a thin through-hole membrane sandwiched between a mirrored array of microfluidic channels and saw-tooth shaped titanium electrodes on the glass. We discuss the design and operation of MFC and show its applicability for cell fusion. The proposed device combines passive hydrodynamic phenomenon and gravitational sedimentation, which allows the transportation and trapping of homotypic and heterotypic cells in large numbers with pairing efficiencies of 75~78% and fusion efficiencies of 73%. Additionally, we also report properties of fused cells from cell biology perspectives, including combined fluorescence-labeled intracellular materials from THP1 and A549, mixed cell morphology, and cell viability. The MFC can be tuned for pairing and fusion of cells with a similar protocol for different cell types. The MFC can be easily disconnected from the test setup for further analysis. Full article

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18 pages, 1513 KiB

Open AccessReview

Fibroblast Memory in Development, Homeostasis and Disease

by Thomas Kirk, Abubkr Ahmed and Emanuel Rognoni

Cells 2021, 10(11), 2840; https://doi.org/10.3390/cells10112840 - 22 Oct 2021

Cited by 38 | Viewed by 5740

Abstract

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally [...] Read more.

Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease. Full article

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20 pages, 9374 KiB

Open AccessFeature PaperArticle

Integrative Analysis to Identify Genes Associated with Stemness and Immune Infiltration in Glioblastoma

by Neerada Meenakshi Warrier, Prasoon Agarwal and Praveen Kumar

Cells 2021, 10(10), 2765; https://doi.org/10.3390/cells10102765 - 15 Oct 2021

Cited by 9 | Viewed by 2518

Abstract

It is imperative to identify the mechanisms that confer stemness to the cancer cells for more effective targeting. Moreover, there are not many studies on the link between stemness characteristics and the immune response in tumours. Therefore, in the current study involving GBM, [...] Read more.

It is imperative to identify the mechanisms that confer stemness to the cancer cells for more effective targeting. Moreover, there are not many studies on the link between stemness characteristics and the immune response in tumours. Therefore, in the current study involving GBM, we started with the study of BIRC5 (one of the rare genes differentially expressed in normal and cancer cells) and CXCR4 (gene involved in the survival and proliferation of CSCs). Together, these genes have not been systematically explored. We used a set of 27 promoter methylated regions in GBM. Our analysis showed that four genes corresponding to these regions, namely EOMES, BDNF, HLA-A, and PECAM1, were involved with BIRC5 and CXCR4. Interestingly, we found EOMES to be very significantly involved in stemness and immunology and it was positively correlated to CXCR4. Additionally, BDNF, which was significant in methylation, was negatively correlated to BIRC5. Full article

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17 pages, 3868 KiB

Open AccessArticle

Early Effects of HTLV-1 Infection on the Activation, Exhaustion, and Differentiation of T-Cells in Humanized NSG Mice

by Otávio de Melo Espíndola, Esther Siteur-van Rijnstra, Esmay Frankin, Kees Weijer, Yme Ubeles van der Velden, Ben Berkhout, Bianca Blom and Julien Villaudy

Cells 2021, 10(10), 2514; https://doi.org/10.3390/cells10102514 - 23 Sep 2021

Cited by 7 | Viewed by 2923

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4⁺ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon [...] Read more.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy of CD4⁺ T-cells associated with HTLV-1 infection. In this study, we used the model of immunodeficient NSG mice reconstituted with a functional human immune system (HIS) to investigate early events in HTLV-1 pathogenesis. Upon infection, human T-cells rapidly increased in the blood and lymphoid tissues, particularly CD4⁺CD25⁺ T-cells. Proliferation of CD4⁺ T-cells in the spleen and mesenteric lymph nodes (MLN) correlated with HTLV-1 proviral load and CD25 expression. In addition, splenomegaly, a common feature of ATLL in humans, was also observed. CD4⁺ and CD8⁺ T-cells predominantly displayed an effector memory phenotype (CD45RA⁻CCR7⁻) and expressed CXCR3 and CCR5 chemokine receptors, suggesting the polarization into a Th1 phenotype. Activated CD8⁺ T-cells expressed granzyme B and perforin; however, the interferon-γ response by these cells was limited, possibly due to elevated PD-1 expression and increased frequency of CD4⁺FoxP3⁺ regulatory T-cells in MLN. Thus, HTLV-1-infected HIS-NSG mice reproduced several characteristics of infection in humans, and it may be helpful to investigate ATLL-related events and to perform preclinical studies. Moreover, aspects of chronic infection were already present at early stages in this experimental model. Collectively, we suggest that HTLV-1 infection modulates host immune responses to favor viral persistence. Full article

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19 pages, 1376 KiB

Open AccessFeature PaperReview

Current Understanding of the Neutrophil Transcriptome in Health and Disease

by Luke W. Garratt

Cells 2021, 10(9), 2406; https://doi.org/10.3390/cells10092406 - 13 Sep 2021

Cited by 29 | Viewed by 8593

Abstract

Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a [...] Read more.

Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas. Full article

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20 pages, 2536 KiB

Open AccessArticle

The Emerging Plasticizer Alternative DINCH and Its Metabolite MINCH Induce Oxidative Stress and Enhance Inflammatory Responses in Human THP-1 Macrophages

by Alexandra Schaffert, Josi Arnold, Isabel Karkossa, Matthias Blüher, Martin von Bergen and Kristin Schubert

Cells 2021, 10(9), 2367; https://doi.org/10.3390/cells10092367 - 9 Sep 2021

Cited by 25 | Viewed by 4272

Abstract

The use of the plasticizer bis(2-ethylhexyl)phthalate (DEHP) and other plasticizers in the manufacture of plastic products has been restricted due to adverse health outcomes such as obesity, metabolic syndrome, and asthma, for which inflammation has been described to be a driving factor. The [...] Read more.

The use of the plasticizer bis(2-ethylhexyl)phthalate (DEHP) and other plasticizers in the manufacture of plastic products has been restricted due to adverse health outcomes such as obesity, metabolic syndrome, and asthma, for which inflammation has been described to be a driving factor. The emerging alternative plasticizer 1,2-cyclohexanedioic acid diisononyl ester (DINCH) still lacks information regarding its potential effects on the immune system. Here, we investigated the effects of DINCH and its naturally occurring metabolite monoisononylcyclohexane-1,2-dicarboxylic acid ester (MINCH) on the innate immune response. Human THP-1 macrophages were exposed to 10 nM–10 μM DINCH or MINCH for 4 h, 16 h, and 24 h. To decipher the underlying mechanism of action, we applied an untargeted proteomic approach that revealed xenobiotic-induced activation of immune-related pathways such as the nuclear factor κB (NF-κB) signaling pathway. Key drivers were associated with oxidative stress, mitochondrial dysfunction, DNA damage repair, apoptosis, and autophagy. We verified increased reactive oxygen species (ROS) leading to cellular damage, NF-κB activation, and subsequent TNF and IL-1β release, even at low nM concentrations. Taken together, DINCH and MINCH induced cellular stress and pro-inflammatory effects in macrophages, which may lead to adverse health effects. Full article

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14 pages, 1949 KiB

Open AccessCommunication

Towards Understanding the Pathogenicity of DROSHA Mutations in Oncohematology

by Dmitrii S. Bug, Artem V. Tishkov, Ivan S. Moiseev, Yuri B. Porozov and Natalia V. Petukhova

Cells 2021, 10(9), 2357; https://doi.org/10.3390/cells10092357 - 8 Sep 2021

Viewed by 2088

Abstract

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders, which are characterized by accumulation of somatic mutations. The acquired mutation burden is suggested to define the pathway and consequent phenotype of the pathology. Recent studies have called attention [...] Read more.

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders, which are characterized by accumulation of somatic mutations. The acquired mutation burden is suggested to define the pathway and consequent phenotype of the pathology. Recent studies have called attention to the role of miRNA biogenesis genes in MDS progression; in particular, the mutational pressure of the DROSHA gene was determined. Therefore, this highlights the importance of studying the impact of all collected missense mutations found within the DROSHA gene in oncohematology that might affect the functionality of the protein. In this study, the selected mutations were extensively examined by computational screening, and the most deleterious were subjected to a further molecular dynamic simulation in order to uncover the molecular mechanism of the structural damage to the protein altering its biological function. The most significant effect was found for variants I625K, L1047S, and H1170D, presumably affecting the endonuclease activity of DROSHA. Such alterations arisen during MDS progression should be taken into consideration as evoking certain clinical traits in the malignifying clonal evolution. Full article

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15 pages, 1216 KiB

Open AccessFeature PaperArticle

CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs

by C. Arnold Spek, Hella L. Aberson, Joe M. Butler, Alex F. de Vos and JanWillem Duitman

Cells 2021, 10(9), 2233; https://doi.org/10.3390/cells10092233 - 28 Aug 2021

Cited by 13 | Viewed by 3390

Abstract

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction [...] Read more.

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolysaccharide (LPS)-induced cytokine production by macrophages. Here, we address this apparent discrepancy and show that the effect of C/EBPδ on cytokine production and macrophage function depends on both the macrophage subtype and the LPS concentration used. Using CRISPR-Cas generated macrophages in which the transactivation domain of C/EBPδ was deleted from the endogenous locus (ΔTAD macrophages), we next show that the context-dependent role of C/EBPδ in macrophage biology relies on compensatory transcriptional activity in the absence of C/EBPδ. We extend these findings by revealing a large discrepancy between transcriptional programs in C/EBPδ knock-out and C/EBPδ transactivation dead (ΔTAD) macrophages implying that compensatory mechanisms do not specifically modify C/EBPδ-dependent inflammatory responses but affect overall macrophage biology. Overall, these data imply that knock-out approaches are not suited for identifying the genuine transcriptional program regulated by C/EBPδ, and we suggest that this phenomenon applies for transcription factor families in general. Full article

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12 pages, 2343 KiB

Open AccessArticle

Time-Dependent Serial Changes of Antigen-Presenting Cell Subsets in the Ocular Surface Are Distinct between Corneal Sterile Inflammation and Allosensitization in a Murine Model

by Kyoung-Woo Kim, Hyun-Ju Lee, Hyeon-Ji Kim and Mee-Kum Kim

Cells 2021, 10(9), 2210; https://doi.org/10.3390/cells10092210 - 26 Aug 2021

Cited by 1 | Viewed by 3415

Abstract

The kinetics of antigen-presenting cells (APCs) vary depending on their resident tissues and the manner of immunization. We investigated the long-term changes in mature APC and T-cell subsets over 4 weeks in the ocular surface in murine models of corneal quiescent or potent [...] Read more.

The kinetics of antigen-presenting cells (APCs) vary depending on their resident tissues and the manner of immunization. We investigated the long-term changes in mature APC and T-cell subsets over 4 weeks in the ocular surface in murine models of corneal quiescent or potent sterile inflammation, and allosensitization using partial (PT), syngeneic (Syn), and allogeneic (Allo) corneal transplantation. In PT, CD11b^intCD11c^hiMHCII^hiCD86^hi cells increased until 4 weeks with an increase in IFNγ^hi T cells. In Syn, both CD11b^intCD11c^hiMHCII^hiCD86^hi and CD11b^hiCD11c^hiMHCII^hiCD86^hi APC subsets increased until 4 weeks with a brief increase in CD69^hi T cells at 2 weeks. In Allo, CD11b^intCD11c^hiMHCII^hiCD86^hi and CD11b^hiCD11c^hiMHCII^hiCD86^hi APC subsets increased until 4 weeks, and an early increase in CD69^hi T cells was observed at 2 weeks followed by a late increase in IFNγ^hi T cells at 4 weeks. The frequency of the IFNγ^hi T cell subset was positively correlated with the frequency of the CD11b^intCD11c^hiMHCII^hiCD86^hi subset, indicating the existence of APC–T cell interaction in the ocular surface. Together, the results indicate that allosensitization in mature APCs leads to T-cell activation in the ocular surface, whereas sterile inflammation merely induces a brief and non-specific T-cell activation in the ocular surface. Full article

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15 pages, 1523 KiB

Open AccessFeature PaperReview

Extracellular Vehicles of Oxygen-Depleted Mesenchymal Stromal Cells: Route to Off-Shelf Cellular Therapeutics?

by Dhir Gala, Sidhesh Mohak and Zsolt Fábián

Cells 2021, 10(9), 2199; https://doi.org/10.3390/cells10092199 - 26 Aug 2021

Cited by 5 | Viewed by 2732

Abstract

Cellular therapy is a promising tool of human medicine to successfully treat complex and challenging pathologies such as cardiovascular diseases or chronic inflammatory conditions. Bone marrow-derived mesenchymal stromal cells (BMSCs) are in the limelight of these efforts, initially, trying to exploit their natural [...] Read more.

Cellular therapy is a promising tool of human medicine to successfully treat complex and challenging pathologies such as cardiovascular diseases or chronic inflammatory conditions. Bone marrow-derived mesenchymal stromal cells (BMSCs) are in the limelight of these efforts, initially, trying to exploit their natural properties by direct transplantation. Extensive research on the therapeutic use of BMSCs shed light on a number of key aspects of BMSC physiology including the importance of oxygen in the control of BMSC phenotype. These efforts also led to a growing number of evidence indicating that the beneficial therapeutic effects of BMSCs can be mediated by BMSC-secreted agents. Further investigations revealed that BMSC-excreted extracellular vesicles could mediate the potentially therapeutic effects of BMSCs. Here, we review our current understanding of the relationship between low oxygen conditions and the effects of BMSC-secreted extracellular vesicles focusing on the possible medical relevance of this interplay. Full article

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9 pages, 717 KiB

Open AccessArticle

Occurrence and Antigenic Specificity of Perinuclear Anti-Neutrophil Cytoplasmic Antibodies (P-ANCA) in Systemic Autoimmune Diseases

by Ourania D. Argyropoulou, Andreas V. Goules, Georgios Boutzios, Alexandra Tsirogianni, Charalampos Sfontouris, Menelaos N. Manoussakis, Panayiotis G. Vlachoyiannopoulos, Athanasios G. Tzioufas and Efstathia K. Kapsogeorgou

Cells 2021, 10(8), 2128; https://doi.org/10.3390/cells10082128 - 19 Aug 2021

Cited by 7 | Viewed by 4549

Abstract

Perinuclear anti-neutrophilic cytoplasmic antibodies (P-ANCA) recognize heterogeneous antigens, including myeloperoxidase (MPO), lactoferrin, elastase, cathepsin-G and bactericidal/permeability-increasing protein. Although P-ANCA have diagnostic utility in vasculitides, they may also be found in patients with various other systemic autoimmune rheumatic diseases (SARDs). Nevertheless, the clinical significance [...] Read more.

Perinuclear anti-neutrophilic cytoplasmic antibodies (P-ANCA) recognize heterogeneous antigens, including myeloperoxidase (MPO), lactoferrin, elastase, cathepsin-G and bactericidal/permeability-increasing protein. Although P-ANCA have diagnostic utility in vasculitides, they may also be found in patients with various other systemic autoimmune rheumatic diseases (SARDs). Nevertheless, the clinical significance and the targets recognized by P-ANCA in such patients remain unclear. For this purpose, herein we investigated the occurrence of ANCA-related antigenic specificities in 82 P-ANCA-positive sera by multiplex ELISA, as well as their association with other autoantibodies. The P-ANCA-positive sera corresponded to patients with vasculitides (n = 24), systemic lupus erythematosus (n = 28), antiphospholipid syndrome (n = 5), Sjögren’s syndrome (n = 7), rheumatoid arthritis (n = 3), systemic scleroderma (n = 1), sarcoidosis (n = 1) and Hashimoto′s thyroiditis (n = 13). In most P-ANCA-positive patients studied (51/82, 62.3%), these autoantibodies occurred in high titers (>1:160). The analysis of P-ANCA-positive sera revealed reactivity to MPO in only 50% of patients with vasculitides, whereas it was infrequent in the other disease groups studied. Reactivity to other P-ANCA-related autoantigens was also rarely detected. Our findings support that high P-ANCA titers occur in SARD. The P-ANCA-positive staining pattern is associated with MPO specificity in vasculitides, while in other autoimmune diseases, it mostly involves unknown autoantigens. Full article

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14 pages, 924 KiB

Open AccessFeature PaperReview

Somatic Mutations and Autoimmunity

by Maha Alriyami and Constantin Polychronakos

Cells 2021, 10(8), 2056; https://doi.org/10.3390/cells10082056 - 11 Aug 2021

Cited by 5 | Viewed by 4357

Abstract

Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in Western countries develops some form of autoimmunity, yet its underlying causes, although intensively studied, are still not fully [...] Read more.

Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in Western countries develops some form of autoimmunity, yet its underlying causes, although intensively studied, are still not fully known, and no curative therapies exist. It is well established that autoimmune diseases have common mechanisms and are caused by both genetic and non-genetic risk factors. One novel risk factor that can contribute to autoimmunity is somatic mutations, in a role parallel to their role in cancer. Somatic mutations are stochastic, de novo, non-inherited mutations. In this hypothesis, the persistent proliferation of self-reactive lymphocytes (that is usually hindered by a series of checkpoints) is permitted, due to somatic mutations in these expanding cells, allowing them to bypass multiple regulatory checkpoints, causing autoimmunity. This novel concept of the contribution of these mutations in non-malignant diseases has recently started to be explored. It proposes a novel paradigm for autoimmunity etiology and could be the missing piece of the autoimmunity puzzle. Full article

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35 pages, 1528 KiB

Open AccessReview

The Immune System Throws Its Traps: Cells and Their Extracellular Traps in Disease and Protection

by Fátima Conceição-Silva, Clarissa S. M. Reis, Paula Mello De Luca, Jessica Leite-Silva, Marta A. Santiago, Alexandre Morrot and Fernanda N. Morgado

Cells 2021, 10(8), 1891; https://doi.org/10.3390/cells10081891 - 26 Jul 2021

Cited by 34 | Viewed by 4913

Abstract

The first formal description of the microbicidal activity of extracellular traps (ETs) containing DNA occurred in neutrophils in 2004. Since then, ETs have been identified in different populations of cells involved in both innate and adaptive immune responses. Much of the knowledge has [...] Read more.

The first formal description of the microbicidal activity of extracellular traps (ETs) containing DNA occurred in neutrophils in 2004. Since then, ETs have been identified in different populations of cells involved in both innate and adaptive immune responses. Much of the knowledge has been obtained from in vitro or ex vivo studies; however, in vivo evaluations in experimental models and human biological materials have corroborated some of the results obtained. Two types of ETs have been described—suicidal and vital ETs, with or without the death of the producer cell. The studies showed that the same cell type may have more than one ETs formation mechanism and that different cells may have similar ETs formation mechanisms. ETs can act by controlling or promoting the mechanisms involved in the development and evolution of various infectious and non-infectious diseases, such as autoimmune, cardiovascular, thrombotic, and neoplastic diseases, among others. This review discusses the presence of ETs in neutrophils, macrophages, mast cells, eosinophils, basophils, plasmacytoid dendritic cells, and recent evidence of the presence of ETs in B lymphocytes, CD4+ T lymphocytes, and CD8+ T lymphocytes. Moreover, due to recently collected information, the effect of ETs on COVID-19 is also discussed. Full article

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16 pages, 1477 KiB

Open AccessArticle

Evaluation of Micro Satellite Instability and Mismatch Repair Status in Different Solid Tumors: A Multicenter Analysis in a Real World Setting

by Umberto Malapelle, Paola Parente, Francesco Pepe, Caterina De Luca, Pasquale Pisapia, Roberta Sgariglia, Mariantonia Nacchio, Gianluca Gragnano, Gianluca Russo, Floriana Conticelli, Claudio Bellevicine, Elena Vigliar, Antonino Iaccarino, Claudia Covelli, Mariangela Balistreri, Celeste Clemente, Giovanni Perrone, Angela Danza, Fabio Scaramuzzi, Matteo Fassan, Giancarlo Troncone and Paolo Graziano Show full author list Hide full author list

Cells 2021, 10(8), 1878; https://doi.org/10.3390/cells10081878 - 24 Jul 2021

Cited by 32 | Viewed by 4985

Abstract

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly [...] Read more.

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the Idylla^TM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors. Full article

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18 pages, 855 KiB

Open AccessFeature PaperReview

Evolution of Cellular Immunity Effector Cells; Perspective on Cytotoxic and Phagocytic Cellular Lineages

by Edna Ayerim Mandujano-Tinoco, Eliya Sultan, Aner Ottolenghi, Orly Gershoni-Yahalom and Benyamin Rosental

Cells 2021, 10(8), 1853; https://doi.org/10.3390/cells10081853 - 22 Jul 2021

Cited by 11 | Viewed by 6149

Abstract

The immune system has evolved to protect organisms from infections caused by bacteria, viruses, and parasitic pathogens. In addition, it provides regenerative capacities, tissue maintenance, and self/non-self recognition of foreign tissues. Phagocytosis and cytotoxicity are two prominent cellular immune activities positioned at the [...] Read more.

The immune system has evolved to protect organisms from infections caused by bacteria, viruses, and parasitic pathogens. In addition, it provides regenerative capacities, tissue maintenance, and self/non-self recognition of foreign tissues. Phagocytosis and cytotoxicity are two prominent cellular immune activities positioned at the base of immune effector function in mammals. Although these immune mechanisms have diversified into a wide heterogeneous repertoire of effector cells, it appears that they share some common cellular and molecular features in all animals, but also some interesting convergent mechanisms. In this review, we will explore the current knowledge about the evolution of phagocytic and cytotoxic immune lineages against pathogens, in the clearance of damaged cells, for regeneration, for histocompatibility recognition, and in killing virally infected cells. To this end, we give different immune examples of multicellular organism models, ranging from the roots of bilateral organisms to chordate invertebrates, comparing to vertebrates’ lineages. In this review, we compare cellular lineage homologies at the cellular and molecular levels. We aim to highlight and discuss the diverse function plasticity within the evolved immune effector cells, and even suggest the costs and benefits that it may imply for organisms with the meaning of greater defense against pathogens but less ability to regenerate damaged tissues and organs. Full article

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Graphical abstract

15 pages, 2221 KiB

Open AccessFeature PaperArticle

β-(1→4)-Mannobiose Acts as an Immunostimulatory Molecule in Murine Dendritic Cells by Binding the TLR4/MD-2 Complex

by Ting-Yu Cheng, Yen-Ju Lin, Wataru Saburi, Stefan Vieths, Stephan Scheurer, Stefan Schülke and Masako Toda

Cells 2021, 10(7), 1774; https://doi.org/10.3390/cells10071774 - 14 Jul 2021

Cited by 8 | Viewed by 5513

Abstract

Some β-mannans, including those in coffee bean and soy, contain a mannose backbone with β-(1→4) bonds. Such mannooligosaccharides could have immunological functions involving direct interaction with immune cells, in addition to acting as prebiotics. This study aimed at assessing the immunological function of [...] Read more.

Some β-mannans, including those in coffee bean and soy, contain a mannose backbone with β-(1→4) bonds. Such mannooligosaccharides could have immunological functions involving direct interaction with immune cells, in addition to acting as prebiotics. This study aimed at assessing the immunological function of mannooligosaccharides with β-(1→4) bond, and elucidating their mechanism of action using bone marrow-derived murine dendritic cells (BMDCs). When BMDCs were stimulated with the mannooligosaccharides, only β-Man-(1→4)-Man significantly induced production of cytokines that included IL-6, IL-10, TNF-α, and IFN-β, and enhanced CD4⁺ T-cell stimulatory capacity. Use of putative receptor inhibitors revealed the binding of β-Man-(1→4)-Man to TLR4/MD2 complex and involvement with the complement C3a receptor (C3aR) for BMDC activation. Interestingly, β-Man-(1→4)-Man prolonged the production of pro-inflammatory cytokines (IL-6 and TNF-α), but not of the IL-10 anti-inflammatory cytokine during extended culture of BMDCs, associated with high glucose consumption. The results suggest that β-Man-(1→4)-Man is an immunostimulatory molecule, and that the promotion of glycolysis could be involved in the production of pro-inflammatory cytokine in β-Man-(1→4)-Man-stimulated BMDCs. This study could contribute to development of immune-boosting functional foods and a novel vaccine adjuvant. Full article

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17 pages, 3256 KiB

Open AccessArticle

In Silico Analysis of the Longevity and Timeline of Individual Germinal Center Reactions in a Primary Immune Response

by Theinmozhi Arulraj, Sebastian C. Binder and Michael Meyer-Hermann

Cells 2021, 10(7), 1736; https://doi.org/10.3390/cells10071736 - 9 Jul 2021

Cited by 1 | Viewed by 2915

Abstract

Germinal centers (GCs) are transient structures in the secondary lymphoid organs, where B cells undergo affinity maturation to produce high affinity memory and plasma cells. The lifetime of GC responses is a critical factor limiting the extent of affinity maturation and efficiency of [...] Read more.

Germinal centers (GCs) are transient structures in the secondary lymphoid organs, where B cells undergo affinity maturation to produce high affinity memory and plasma cells. The lifetime of GC responses is a critical factor limiting the extent of affinity maturation and efficiency of antibody responses. While the average lifetime of overall GC reactions in a lymphoid organ is determined experimentally, the lifetime of individual GCs has not been monitored due to technical difficulties in longitudinal analysis. In silico analysis of the contraction phase of GC responses towards primary immunization with sheep red blood cells suggested that if individual GCs had similar lifetimes, the data would be consistent only when new GCs were formed until a very late phase after immunization. Alternatively, there could be a large variation in the lifetime of individual GCs suggesting that both long and short-lived GCs might exist in the same lymphoid organ. Simulations predicted that such differences in the lifetime of GCs could arise due to variations in antigen availability and founder cell composition. These findings identify the potential factors limiting GC lifetime and contribute to an understanding of overall GC responses from the perspective of individual GCs in a primary immune response. Full article

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18 pages, 2362 KiB

Open AccessReview

Apoptosis in the Pancreatic Cancer Tumor Microenvironment—The Double-Edged Sword of Cancer-Associated Fibroblasts

by Ester Pfeifer, Joy M. Burchell, Francesco Dazzi, Debashis Sarker and Richard Beatson

Cells 2021, 10(7), 1653; https://doi.org/10.3390/cells10071653 - 1 Jul 2021

Cited by 12 | Viewed by 5611

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF. Full article

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17 pages, 31330 KiB

Open AccessArticle

Systemic T Cell Exhaustion Dynamics Is Linked to Early High Mobility Group Box Protein 1 (HMGB1) Driven Hyper-Inflammation in a Polytrauma Rat Model

by Preeti J. Muire, Martin G. Schwacha and Joseph C. Wenke

Cells 2021, 10(7), 1646; https://doi.org/10.3390/cells10071646 - 30 Jun 2021

Cited by 16 | Viewed by 2951

Abstract

We previously reported an early surge in high mobility group box protein 1 (HMGB1) levels in a polytrauma (PT) rat model. This study investigates the association of HMGB1 levels in mediating PT associated dysregulated immune responses and its influence on the cellular levels [...] Read more.

We previously reported an early surge in high mobility group box protein 1 (HMGB1) levels in a polytrauma (PT) rat model. This study investigates the association of HMGB1 levels in mediating PT associated dysregulated immune responses and its influence on the cellular levels of receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). Using the same PT rat model treated with anti-HMGB1 polyclonal antibody, we evaluated changes in circulating inflammatory cytokines, monocytes/macrophages and T cells dynamics and cell surface expression of RAGE and TLR4 at 1, 3, and 7 days post-trauma (dpt) in blood and spleen. Notably, PT rats demonstrating T helper (Th)1 and Th2 cells type early hyper-inflammatory responses also exhibited increased monocyte/macrophage counts and diminished T cell counts in blood and spleen. In blood, expression of RAGE and TLR4 receptors was elevated on CD68⁺ monocyte/macrophages and severely diminished on CD4⁺ and CD8⁺ T cells. Neutralization of HMGB1 significantly decreased CD68⁺ monocyte/macrophage counts and increased CD4⁺ and CD8⁺ T cells, but not γδ⁺TCR T cells in circulation. Most importantly, RAGE and TLR4 expressions were restored on CD4⁺ and CD8⁺ T cells in treated PT rats. Overall, findings suggest that in PT, the HMGB1 surge is responsible for the onset of T cell exhaustion and dysfunction, leading to diminished RAGE and TLR4 surface expression, thereby possibly hindering the proper functioning of T cells. Full article

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25 pages, 1347 KiB

Open AccessReview

Angiogenic Properties of NK Cells in Cancer and Other Angiogenesis-Dependent Diseases

by Dorota M. Radomska-Leśniewska, Agata Białoszewska and Paweł Kamiński

Cells 2021, 10(7), 1621; https://doi.org/10.3390/cells10071621 - 29 Jun 2021

Cited by 28 | Viewed by 4277

Abstract

The pathogenesis of many serious diseases, including cancer, is closely related to disturbances in the angiogenesis process. Angiogenesis is essential for the progression of tumor growth and metastasis. The tumor microenvironment (TME) has immunosuppressive properties, which contribute to tumor expansion and angiogenesis. Similarly, [...] Read more.

The pathogenesis of many serious diseases, including cancer, is closely related to disturbances in the angiogenesis process. Angiogenesis is essential for the progression of tumor growth and metastasis. The tumor microenvironment (TME) has immunosuppressive properties, which contribute to tumor expansion and angiogenesis. Similarly, the uterine microenvironment (UME) exerts a tolerogenic (immunosuppressive) and proangiogenic effect on its cells, promoting implantation and development of the embryo and placenta. In the TME and UME natural killer (NK) cells, which otherwise are capable of killing target cells autonomously, enter a state of reduced cytotoxicity or anergy. Both TME and UME are rich with factors (e.g., TGF-β, glycodelin, hypoxia), which support a conversion of NK cells to the low/non-cytotoxic, proangiogenic CD56^brightCD16^low phenotype. It is plausible that the phenomenon of acquiring proangiogenic and low cytotoxic features by NK cells is not only limited to cancer but is a common feature of different angiogenesis-dependent diseases (ADDs). In this review, we will discuss the role of NK cells in angiogenesis disturbances associated with cancer and other selected ADDs. Expanding the knowledge of the mechanisms responsible for angiogenesis and its disorders contributes to a better understanding of ADDs and may have therapeutic implications. Full article

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21 pages, 6464 KiB

Open AccessFeature PaperReview

Strength and Numbers: The Role of Affinity and Avidity in the ‘Quality’ of T Cell Tolerance

by Sébastien This, Stefanie F. Valbon, Marie-Ève Lebel and Heather J. Melichar

Cells 2021, 10(6), 1530; https://doi.org/10.3390/cells10061530 - 17 Jun 2021

Cited by 3 | Viewed by 5209

Abstract

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. [...] Read more.

The ability of T cells to identify foreign antigens and mount an efficient immune response while limiting activation upon recognition of self and self-associated peptides is critical. Multiple tolerance mechanisms work in concert to prevent the generation and activation of self-reactive T cells. T cell tolerance is tightly regulated, as defects in these processes can lead to devastating disease; a wide variety of autoimmune diseases and, more recently, adverse immune-related events associated with checkpoint blockade immunotherapy have been linked to a breakdown in T cell tolerance. The quantity and quality of antigen receptor signaling depend on a variety of parameters that include T cell receptor affinity and avidity for peptide. Autoreactive T cell fate choices (e.g., deletion, anergy, regulatory T cell development) are highly dependent on the strength of T cell receptor interactions with self-peptide. However, less is known about how differences in the strength of T cell receptor signaling during differentiation influences the ‘function’ and persistence of anergic and regulatory T cell populations. Here, we review the literature on this subject and discuss the clinical implications of how T cell receptor signal strength influences the ‘quality’ of anergic and regulatory T cell populations. Full article

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11 pages, 15032 KiB

Open AccessArticle

Extracellular Soluble Membranes from Retinal Pigment Epithelial Cells Mediate Apoptosis in Macrophages

by Nayan Sanjiv, Pawarissara Osathanugrah, Emma Fraser, Tat Fong Ng and Andrew W. Taylor

Cells 2021, 10(5), 1193; https://doi.org/10.3390/cells10051193 - 13 May 2021

Cited by 7 | Viewed by 2765

Abstract

A central characterization of retinal immunobiology is the prevention of proinflammatory activity by macrophages. The retinal pigment epithelial cells (RPEs) are a major source of soluble anti-inflammatory factors. This includes a soluble factor that induces macrophage apoptosis when the activity of the immunomodulating [...] Read more.

A central characterization of retinal immunobiology is the prevention of proinflammatory activity by macrophages. The retinal pigment epithelial cells (RPEs) are a major source of soluble anti-inflammatory factors. This includes a soluble factor that induces macrophage apoptosis when the activity of the immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) is neutralized. In this manuscript, isolated extracellular soluble membranes (ESMs) from primary RPE were assayed to see if they could be the soluble mediator of apoptosis. Our results demonstrated that RPE ESMs mediated the induction of macrophage apoptosis that was suppressed by α-MSH. In contrast, the RPE line ARPE-19, cultured under conditions that induce similar anti-inflammatory activity to primary RPEs, did not activate apoptosis in the macrophages. Moreover, only the ESMs from primary RPE cultures, and not those from the ARPE-19 cell cultures, expressed mFasL. The results demonstrate that RPE ESMs are a soluble mediator of apoptosis and that this may be a mechanism by which the RPEs select for the survival of α-MSH-induced suppressor cells. Full article

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18 pages, 6774 KiB

Open AccessArticle

New Treatment Strategy Targeting Galectin-1 against Thyroid Cancer

by Laetitia Gheysen, Laura Soumoy, Anne Trelcat, Laurine Verset, Fabrice Journe and Sven Saussez

Cells 2021, 10(5), 1112; https://doi.org/10.3390/cells10051112 - 5 May 2021

Cited by 14 | Viewed by 3936

Abstract

Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer [...] Read more.

Although the overall survival rate of papillary or follicular thyroid cancers is good, anaplastic carcinomas and radio iodine refractory cancers remain a significant therapeutic challenge. Galectin-1 (Gal-1) is overexpressed in tumor cells and tumor-associated endothelial cells, and is broadly implicated in angiogenesis, cancer cell motility and invasion, and immune system escape. Our team has previously demonstrated a higher serum level of Gal-1 in patients with differentiated thyroid cancers versus healthy patients, and explored, by a knockdown strategy, the effect of Gal-1 silencing on cell proliferation and invasion in vitro, and on tumor and metastasis development in vivo. OTX008 is a calixarene derivative designed to bind the Gal-1 amphipathic β-sheet conformation and has previously demonstrated anti-proliferative and anti-invasive properties in several cancer cell lines including colon, breast, head and neck, and prostate cancer lines. In the current work, the impacts of OTX008 were evaluated in six thyroid cancer cell lines, and significant inhibitions of proliferation, migration, and invasion were observed in all lines expressing high Gal-1 levels. In addition, the signaling pathways affected by this drug were examined using RPPA (reverse phase protein array) and phosphoprotein expression assays, and opposite regulation of eNos, PYK2, and HSP27 by OTX008 was detected by comparing the two anaplastic lines 8505c and CAL 62. Finally, the sensitive 8505c line was xenografted in nude mice, and 3 weeks of OTX008 treatment (5 mg/kg/day) demonstrated a significant reduction in tumor and lung metastasize sizes without side effects. Overall, OXT008 showed significant anti-cancer effects both in vitro and in vivo in thyroid cancer lines expressing Gal-1, supporting further investigation of the molecular mechanisms of the drug and future clinical trials in patients with anaplastic thyroid cancer. Full article

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14 pages, 11199 KiB

Open AccessArticle

Transcriptional Regulation of Thrombin-Induced Endothelial VEGF Induction and Proangiogenic Response

by Rusan Catar, Guido Moll, Isa Hosp, Michele Simon, Christian Luecht, Hongfan Zhao, Dashan Wu, Lei Chen, Julian Kamhieh-Milz, Katarzyna Korybalska, Daniel Zickler and Janusz Witowski

Cells 2021, 10(4), 910; https://doi.org/10.3390/cells10040910 - 15 Apr 2021

Cited by 26 | Viewed by 6379

Abstract

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and [...] Read more.

Thrombin, the ligand of the protease-activated receptor 1 (PAR1), is a well-known stimulator of proangiogenic responses in vascular endothelial cells (ECs), which are mediated through the induction of vascular endothelial growth factor (VEGF). However, the transcriptional events underlying this thrombin-induced VEGF induction and angiogenic response are less well understood at present. As reported here, we conducted detailed promotor activation and signal transduction pathway studies in human microvascular ECs, to decipher the transcription factors and the intracellular signaling events underlying the thrombin and PAR-1-induced endothelial VEGF induction. We found that c-FOS is a key transcription factor controlling thrombin-induced EC VEGF synthesis and angiogenesis. Upon the binding and internalization of its G-protein-coupled PAR-1 receptor, thrombin triggers ERK1/2 signaling and activation of the nuclear AP-1/c-FOS transcription factor complex, which then leads to VEGF transcription, extracellular secretion, and concomitant proangiogenic responses of ECs. In conclusion, exposure of human microvascular ECs to thrombin triggers signaling through the PAR-1–ERK1/2–AP-1/c-FOS axis to control VEGF gene transcription and VEGF-induced angiogenesis. These observations offer a greater understanding of endothelial responses to thromboinflammation, which may help to interpret the results of clinical trials tackling the conditions associated with endothelial injury and thrombosis. Full article

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17 pages, 3729 KiB

Open AccessArticle

Sirtuin 2 Dysregulates Autophagy in High-Fat-Exposed Immune-Tolerant Macrophages

by Sanjoy Roychowdhury, Anugraha Gandhirajan, Christopher Kibler, Xianfeng Wang and Vidula Vachharajani

Cells 2021, 10(4), 731; https://doi.org/10.3390/cells10040731 - 26 Mar 2021

Cited by 16 | Viewed by 3133

Abstract

Obesity increases morbidity and resource utilization in sepsis patients. The immune response in sepsis transitions from an endotoxin-responsive hyper- to an endotoxin-tolerant hypo-inflammatory phase. The majority of sepsis mortality occurs during hypo-inflammation. We reported prolonged hypo-inflammation with increased sirtuin 2 (SIRT2) expression in [...] Read more.

Obesity increases morbidity and resource utilization in sepsis patients. The immune response in sepsis transitions from an endotoxin-responsive hyper- to an endotoxin-tolerant hypo-inflammatory phase. The majority of sepsis mortality occurs during hypo-inflammation. We reported prolonged hypo-inflammation with increased sirtuin 2 (SIRT2) expression in obese-septic mice. The effect of direct exposure to high-fat/free fatty acid (FFA) and the role of SIRT2 in immune cells during the transition to hypo-inflammation is not well-understood. Autophagy, a degradation process of damaged protein/organelles, is dysregulated during sepsis. Here, we investigated the effect of direct FFA exposure and the role of SIRT2 expression on autophagy as macrophages transition from hyper-to hypo-inflammation. We found, FFA-exposed RAW 264.7 cells with lipopolysaccharide (LPS) stimulation undergo endotoxin-sensitive (“sensitive”) hyper- followed by endotoxin tolerant (“tolerant”) hypo-inflammatory phases; SIRT2 expression increases significantly in tolerant cells. Autophagy proteins LC3b-II, and beclin-1 increase in FFA-sensitive and decrease in tolerant cells; p62 expressions continue to accumulate in tolerant cells. We observed that SIRT2 directly deacetylates α-tubulin and impairs autophagy clearance. Importantly, we find SIRT2 inhibitor AK-7 treatment during endotoxin tolerant phase reverses autophagy dysregulation with improved autophagy clearance in FFA-tolerant cells. Thus, we report impaired autophagosome formation and autophagy clearance via increased SIRT2 expression in FFA-exposed tolerant macrophages. Full article

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17 pages, 1613 KiB

Open AccessFeature PaperArticle

The Phosphoarginine Phosphatase PtpB from Staphylococcus aureus Is Involved in Bacterial Stress Adaptation during Infection

by Mohamed Ibrahem Elhawy, Sylvaine Huc-Brandt, Linda Pätzold, Laila Gannoun-Zaki, Ahmed Mohamed Mostafa Abdrabou, Markus Bischoff and Virginie Molle

Cells 2021, 10(3), 645; https://doi.org/10.3390/cells10030645 - 14 Mar 2021

Cited by 6 | Viewed by 3724

Abstract

Staphylococcus aureus continues to be a public health threat, especially in hospital settings. Studies aimed at deciphering the molecular and cellular mechanisms that underlie pathogenesis, host adaptation, and virulence are required to develop effective treatment strategies. Numerous host-pathogen interactions were found to be [...] Read more.

Staphylococcus aureus continues to be a public health threat, especially in hospital settings. Studies aimed at deciphering the molecular and cellular mechanisms that underlie pathogenesis, host adaptation, and virulence are required to develop effective treatment strategies. Numerous host-pathogen interactions were found to be dependent on phosphatases-mediated regulation. This study focused on the analysis of the role of the low-molecular weight phosphatase PtpB, in particular, during infection. Deletion of ptpB in S. aureus strain SA564 significantly reduced the capacity of the mutant to withstand intracellular killing by THP-1 macrophages. When injected into normoglycemic C57BL/6 mice, the SA564 ΔptpB mutant displayed markedly reduced bacterial loads in liver and kidney tissues in a murine S. aureus abscess model when compared to the wild type. We also observed that PtpB phosphatase-activity was sensitive to oxidative stress. Our quantitative transcript analyses revealed that PtpB affects the transcription of various genes involved in oxidative stress adaptation and infectivity. Thus, this study disclosed first insights into the physiological role of PtpB during host interaction allowing us to link phosphatase-dependent regulation to oxidative bacterial stress adaptation during infection. Full article

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15 pages, 1234 KiB

Open AccessFeature PaperReview

Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly

by Weikan Wang, Rachel Thomas, Jiyoung Oh and Dong-Ming Su

Cells 2021, 10(3), 628; https://doi.org/10.3390/cells10030628 - 12 Mar 2021

Cited by 31 | Viewed by 7659

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly. Full article

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15 pages, 1909 KiB

Open AccessArticle

Growth Arrest-Specific Gene 6 Administration Ameliorates Sepsis-Induced Organ Damage in Mice and Reduces ROS Formation In Vitro

by Livia Salmi, Francesco Gavelli, Filippo Patrucco, Mattia Bellan, Pier Paolo Sainaghi, Gian Carlo Avanzi and Luigi Mario Castello

Cells 2021, 10(3), 602; https://doi.org/10.3390/cells10030602 - 9 Mar 2021

Cited by 9 | Viewed by 3314

Abstract

Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK [...] Read more.

Sepsis is a widespread life-threatening disease, with a high mortality rate due to inflammation-induced multiorgan failure (MOF). Thus, new effective modulators of the immune response are urgently needed to ameliorate the outcome of septic patients. As growth arrest-specific gene 6 (Gas6)/Tyro3, Axl, MerTK (TAM) receptors signaling has shown immunomodulatory activity in sepsis, here we sought to determine whether Gas6 protein injection could mitigate MOF in a cecal slurry mouse model of sepsis. Mice, divided into different groups according to treatment—i.e., placebo (B), ampicillin (BA), Gas6 alone (BG), and ampicillin plus Gas6 (BAG)—were assessed for vitality, histopathology and cytokine expression profile as well as inducible nitric oxide synthase (iNOS), ALT and LDH levels. BAG-treated mice displayed milder kidney and lung damage and reduced levels of cytokine expression and iNOS in the lungs compared to BA-treated mice. Notably, BAG-treated mice showed lower LDH levels compared to controls. Lastly, BAG-treated cells of dendritic, endothelial or monocytic origin displayed reduced ROS formation and increased cell viability, with a marked upregulation of mitochondrial activity. Altogether, our findings indicate that combined treatment with Gas6 and antibiotics ameliorates sepsis-induced organ damage and reduces systemic LDH levels in mice, suggesting that Gas6 intravenous injection may be a viable therapeutic option in sepsis. Full article

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8 pages, 1185 KiB

Open AccessCommunication

Ambiguity about Splicing Factor 3b Subunit 3 (SF3B3) and Sin3A Associated Protein 130 (SAP130)

by Paula I. Metselaar, Celine Hos, Olaf Welting, Jos A. Bosch, Aletta D. Kraneveld, Wouter J. de Jonge and Anje A. Te Velde

Cells 2021, 10(3), 590; https://doi.org/10.3390/cells10030590 - 8 Mar 2021

Cited by 4 | Viewed by 3223

Abstract

In 2020, three articles were published on a protein that can activate the immune system by binding to macrophage-inducible C-type lectin receptor (Mincle). In the articles, the protein was referred to as ‘SAP130, a subunit of the histone deacetylase complex.’ However, the Mincle [...] Read more.

In 2020, three articles were published on a protein that can activate the immune system by binding to macrophage-inducible C-type lectin receptor (Mincle). In the articles, the protein was referred to as ‘SAP130, a subunit of the histone deacetylase complex.’ However, the Mincle ligand the authors aimed to investigate is splicing factor 3b subunit 3 (SF3B3). This splicing factor is unrelated to SAP130 (Sin3A associated protein 130, a subunit of the histone deacetylase-dependent Sin3A corepressor complex). The conclusions in the three articles were formulated for SF3B3, while the researchers used qPCR primers and antibodies against SAP130. We retraced the origins of the ambiguity about the two proteins and found that Online Mendelian Inheritance in Man (OMIM) added a Nature publication on SF3B3 as a reference for Sin3A associated protein 130 in 2016. Subsequently, companies such as Abcam referred to OMIM and the Nature article in their products for both SF3B3 and SAP130. In turn, the mistake by OMIM followed in the persistent and confusing use of ‘SAP130′ (spliceosome-associated protein 130) as an alternative symbol for SF3B3. With this report, we aim to eliminate the persistent confusion and separate the literature regarding the two proteins. Full article

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11 pages, 2795 KiB

Open AccessArticle

CERI, CEFX, and CPI: Largely Improved Positive Controls for Testing Antigen-Specific T Cell Function in PBMC Compared to CEF

by Alexander A. Lehmann, Pedro A. Reche, Ting Zhang, Maneewan Suwansaard and Paul V. Lehmann

Cells 2021, 10(2), 248; https://doi.org/10.3390/cells10020248 - 27 Jan 2021

Cited by 9 | Viewed by 7249

Abstract

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of [...] Read more.

Monitoring antigen-specific T cell immunity relies on functional tests that require T cells and antigen presenting cells to be uncompromised. Drawing of blood, its storage and shipment from the clinical site to the test laboratory, and the subsequent isolation, cryopreservation and thawing of peripheral blood mononuclear cells (PBMCs) before the actual test is performed can introduce numerous variables that may jeopardize the results. Therefore, no T cell test is valid without assessing the functional fitness of the PBMC being utilized. This can only be accomplished through the inclusion of positive controls that actually evaluate the performance of the antigen-specific T cell and antigen presenting cell (APC) compartments. For Caucasians, CEF peptides have been commonly used to this extent. Moreover, CEF peptides only measure CD8 cell functionality. We introduce here universal CD8+ T cell positive controls without any racial bias, as well as positive controls for the CD4+ T cell and APC compartments. In summary, we offer new tools and strategies for the assessment of PBMC functional fitness required for reliable T cell immune monitoring. Full article

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2020

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29 pages, 1730 KiB

Open AccessReview

Checkpoint Inhibitors and Engineered Cells: New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies

by Massimo Giuliani and Alessandro Poggi

Cells 2020, 9(7), 1578; https://doi.org/10.3390/cells9071578 - 29 Jun 2020

Cited by 10 | Viewed by 4250

Abstract

Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment [...] Read more.

Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignancies to block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors. Full article

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