Biomedicines

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Open AccessEditorial

Macrophages in Health and Non-Infectious Disease 2.0

by Evgeny E. Bezsonov, Alexei Gratchev and Alexander N. Orekhov

Biomedicines 2022, 10(6), 1215; https://doi.org/10.3390/biomedicines10061215 - 24 May 2022

Viewed by 1467

Abstract

This Special Issue (SI) has collected the most recent publications on the mechanisms that macrophages use to regulate homeostasis and their involvement in the pathogenesis of various non-infectious diseases [...] Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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Research

Jump to: Editorial, Review

17 pages, 5813 KiB

Open AccessArticle

Targeted Accumulation of Macrophages Induced by Microbeam Irradiation in a Tissue-Dependent Manner

by Verdiana Trappetti, Jennifer Fazzari, Cristian Fernandez-Palomo, Lloyd Smyth, Marine Potez, Nahoko Shintani, Bettina de Breuyn Dietler, Olga A. Martin and Valentin Djonov

Biomedicines 2022, 10(4), 735; https://doi.org/10.3390/biomedicines10040735 - 22 Mar 2022

Cited by 4 | Viewed by 3302

Abstract

Radiation therapy (RT) is a vital component of multimodal cancer treatment, and its immunomodulatory effects are a major focus of current therapeutic strategies. Macrophages are some of the first cells recruited to sites of radiation-induced injury where they can aid in tissue repair, [...] Read more.

Radiation therapy (RT) is a vital component of multimodal cancer treatment, and its immunomodulatory effects are a major focus of current therapeutic strategies. Macrophages are some of the first cells recruited to sites of radiation-induced injury where they can aid in tissue repair, propagate radiation-induced fibrogenesis and influence tumour dynamics. Microbeam radiation therapy (MRT) is a unique, spatially fractionated radiation modality that has demonstrated exceptional tumour control and reduction in normal tissue toxicity, including fibrosis. We conducted a morphological analysis of MRT-irradiated normal liver, lung and skin tissues as well as lung and melanoma tumours. MRT induced distinct patterns of DNA damage, reflecting the geometry of the microbeam array. Macrophages infiltrated these regions of peak dose deposition at variable timepoints post-irradiation depending on the tissue type. In normal liver and lung tissue, macrophages clearly demarcated the beam path by 48 h and 7 days post-irradiation, respectively. This was not reflected, however, in normal skin tissue, despite clear DNA damage marking the beam path. Persistent DNA damage was observed in MRT-irradiated lung carcinoma, with an accompanying geometry-specific influx of mixed M1/M2-like macrophage populations. These data indicate the unique potential of MRT as a tool to induce a remarkable accumulation of macrophages in an organ/tissue-specific manner. Further characterization of these macrophage populations is warranted to identify their organ-specific roles in normal tissue sparing and anti-tumour responses. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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13 pages, 1355 KiB

Open AccessArticle

Roux-en-Y Gastric Bypass Modulates AMPK, Autophagy and Inflammatory Response in Leukocytes of Obese Patients

by Zaida Abad-Jiménez, Sandra López-Domènech, Celia García-Gargallo, Teresa Vezza, Segundo Ángel Gómez-Abril, Carlos Morillas, Pedro Díaz-Pozo, Rosa Falcón, Celia Bañuls, Víctor M. Víctor and Milagros Rocha

Biomedicines 2022, 10(2), 430; https://doi.org/10.3390/biomedicines10020430 - 12 Feb 2022

Cited by 8 | Viewed by 2879

Abstract

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic [...] Read more.

Obesity is characterized by low-grade chronic inflammation, metabolic overload, and impaired endothelial and cardiovascular function. Roux-en-Y gastric bypass (RYGB) results in amelioration of the pro-oxidant status of leukocytes and the metabolic profile. Nevertheless, little is known about the precise mechanism that drives systemic and metabolic improvements following bariatric surgery. In this cohort study, we investigated the effect of RYGB on molecular pathways involving energy homeostasis in leukocytes in 43 obese subjects one year after surgery. In addition to clinical and biochemical parameters, we determined protein expression of systemic proinflammatory cytokines by Luminex^®, different markers of inflammation, endoplasmic reticulum (ER) stress, autophagy/mitophagy by western blot, and mitochondrial membrane potential by fluorescence imaging. Bariatric surgery induced an improvement in metabolic outcomes that was accompanied by a systemic drop in hsCRP, IL6, and IL1β levels, and a slowing down of intracellular inflammatory pathways in leukocytes (NF-κB and MCP-1), an increase in AMPK content, a reduction of ER stress (ATF6 and CHOP), augmented autophagy/mitophagy markers (Beclin 1, ATG5, LC3-I, LC3-II, NBR1, and PINK1), and a decrease of mitochondrial membrane potential. These findings shed light on the specific molecular mechanisms by which RYGB facilitates metabolic improvements, highlighting the relevance of pathways involving energy homeostasis as key mediators of these outcomes. In addition, since leukocytes are particularly exposed to physiological changes, they could be used in routine clinical practice as a good sensor of the whole body’s responses. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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17 pages, 3155 KiB

Open AccessArticle

CD14 Is Involved in the Interferon Response of Human Macrophages to Rubella Virus Infection

by Erik Schilling, Lukas Pfeiffer, Sunna Hauschildt, Ulrike Koehl and Claudia Claus

Biomedicines 2022, 10(2), 266; https://doi.org/10.3390/biomedicines10020266 - 26 Jan 2022

Cited by 3 | Viewed by 3512

Abstract

Macrophages (MΦ) as specialized immune cells are involved in rubella virus (RuV) pathogenesis and enable the study of its interaction with the innate immune system. A similar replication kinetics of RuV in the two human MΦ types, the pro-inflammatory M1-like (or GM-MΦ) and [...] Read more.

Macrophages (MΦ) as specialized immune cells are involved in rubella virus (RuV) pathogenesis and enable the study of its interaction with the innate immune system. A similar replication kinetics of RuV in the two human MΦ types, the pro-inflammatory M1-like (or GM-MΦ) and anti-inflammatory M2-like (M-MΦ), was especially in M-MΦ accompanied by a reduction in the expression of the innate immune receptor CD14. Similar to RuV infection, exogenous interferon (IFN) β induced a loss of glycolytic reserve in M-MΦ, but in contrast to RuV no noticeable influence on CD14 expression was detected. We next tested the contribution of CD14 to the generation of cytokines/chemokines during RuV infection of M-MΦ through the application of anti-CD14 blocking antibodies. Blockage of CD14 prior to RuV infection enhanced generation of virus progeny. In agreement with this observation, the expression of IFNs was significantly reduced in comparison to the isotype control. Additionally, the expression of TNF-α was slightly reduced, whereas the chemokine CXCL10 was not altered. In conclusion, the observed downmodulation of CD14 during RuV infection of M-MΦ appears to contribute to virus-host-adaptation through a reduction of the IFN response. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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26 pages, 5047 KiB

Open AccessArticle

Transcriptomic and Lipidomic Mapping of Macrophages in the Hub of Chronic Beta-Adrenergic-Stimulation Unravels Hypertrophy-, Proliferation-, and Lipid Metabolism-Related Genes as Novel Potential Markers of Early Hypertrophy or Heart Failure

by Sophie Nadaud, Mathilde Flamant, Wilfried Le Goff, Elise Balse and Catherine Pavoine

Biomedicines 2022, 10(2), 221; https://doi.org/10.3390/biomedicines10020221 - 20 Jan 2022

Cited by 2 | Viewed by 3512

Abstract

Sympathetic nervous system overdrive with chronic release of catecholamines is the most important neurohormonal mechanism activated to maintain cardiac output in response to heart stress. Beta-adrenergic signaling behaves first as a compensatory pathway improving cardiac contractility and maladaptive remodeling but becomes dysfunctional leading [...] Read more.

Sympathetic nervous system overdrive with chronic release of catecholamines is the most important neurohormonal mechanism activated to maintain cardiac output in response to heart stress. Beta-adrenergic signaling behaves first as a compensatory pathway improving cardiac contractility and maladaptive remodeling but becomes dysfunctional leading to pathological hypertrophy and heart failure (HF). Cardiac remodeling is a complex inflammatory syndrome where macrophages play a determinant role. This study aimed at characterizing the temporal transcriptomic evolution of cardiac macrophages in mice subjected to beta-adrenergic-stimulation using RNA sequencing. Owing to a comprehensive bibliographic analysis and complementary lipidomic experiments, this study deciphers typical gene profiles in early compensated hypertrophy (ECH) versus late dilated remodeling related to HF. We uncover cardiac hypertrophy- and proliferation-related transcription programs typical of ECH or HF macrophages and identify lipid metabolism-associated and Na⁺ or K⁺ channel-related genes as markers of ECH and HF macrophages, respectively. In addition, our results substantiate the key time-dependent role of inflammatory, metabolic, and functional gene regulation in macrophages during beta-adrenergic dependent remodeling. This study provides important and novel knowledge to better understand the prevalent key role of resident macrophages in response to chronically activated beta-adrenergic signaling, an effective diagnostic and therapeutic target in failing hearts. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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15 pages, 3145 KiB

Open AccessArticle

Candida albicans Induces Foaming and Inflammation in Macrophages through FABP4: Its Implication for Atherosclerosis

by Mohammed Haider, Fatema Al-Rashed, Zahraa Albaqsumi, Khaled Alobaid, Rawan Alqabandi, Fahd Al-Mulla and Rasheed Ahmad

Biomedicines 2021, 9(11), 1567; https://doi.org/10.3390/biomedicines9111567 - 29 Oct 2021

Cited by 8 | Viewed by 3007

Abstract

Atherosclerosis is a chronic degenerative disorder characterized by lipid-dense plaques and low-grade inflammation affecting arterial walls. Foamy macrophages are important in the formation of atherosclerotic plaques and the induction of low-grade inflammation. The presence of lipid-laden macrophages has occurred in infections caused by [...] Read more.

Atherosclerosis is a chronic degenerative disorder characterized by lipid-dense plaques and low-grade inflammation affecting arterial walls. Foamy macrophages are important in the formation of atherosclerotic plaques and the induction of low-grade inflammation. The presence of lipid-laden macrophages has occurred in infections caused by opportunistic pathogens. Candida albicans is the major cause of candidiasis in immunocompromised patients, including those with diabetes mellitus. However, the role played by C. albicans in macrophage foaming and the associated inflammation is poorly understood. We investigated whether C. albicans induces foaming along with inflammation in macrophages and, if so, by which mechanism(s). We incubated THP-1 macrophages with heat-killed C. albicans (HKCA). HKCA-induced lipid accumulation in macrophages along with increased expression of inflammatory markers, including CD11b and CD11c or expression and secretion of IL-1β. HKCA also increased the expression of PPARγ, CD36, and FABP4 in macrophages. Mechanistically, we found that the foamy and inflammatory macrophage phenotype induced by HKCA requires FABP4 because disruption of FABP4 in macrophages either by chemical inhibitor BMS309404 or small interfering RNA (siRNA) abrogated foam cell formation and expression of inflammatory markers CD11b, CD11c, and IL-1β. Furthermore, HKCA-treated macrophages displayed high expression and secretion of MMP-9. Inhibition of FABP4 resulted in suppression of HCKA-induced MMP-9 production. Overall, our results demonstrate that C. albicans induces foam cell formation, inflammation, and MMP-9 expression in macrophages via the upregulation of FABP4, which may constitute a novel therapeutic target for treating C. albicans-induced atherosclerosis. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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15 pages, 1861 KiB

Open AccessArticle

Increased Lipid Peroxidation May Be Linked to Ferritin Levels Elevation in Adult-Onset Still’s Disease

by Po-Ku Chen, Kai-Jieh Yeo, Po-Hao Huang, Shih-Hsin Chang, Ching-Kun Chang, Joung-Liang Lan and Der-Yuan Chen

Biomedicines 2021, 9(11), 1508; https://doi.org/10.3390/biomedicines9111508 - 20 Oct 2021

Cited by 5 | Viewed by 2554

Abstract

Lipid peroxidation (LPO) and hyper-ferritinemia are involved in inflammatory responses. Although hyper-ferritinemia is a characteristic of AOSD, its link to LPO remains unclear. We investigated the association between LPO and ferritin expression, and evaluated the relationship between LPO-related metabolites and inflammatory parameters. Mean [...] Read more.

Lipid peroxidation (LPO) and hyper-ferritinemia are involved in inflammatory responses. Although hyper-ferritinemia is a characteristic of AOSD, its link to LPO remains unclear. We investigated the association between LPO and ferritin expression, and evaluated the relationship between LPO-related metabolites and inflammatory parameters. Mean fluorescence intensity (MFI) of LPO (C11-Biodipy^581/591)-expressing PBMCs/monocytes in AOSD patients and healthy control (HC) subjects was determined by flow-cytometry analysis. Expression of ferritin and cytokines on PBMCs/macrophages was examined by immunoblotting. Plasma levels of LPO-related metabolites and cytokines were determined by ELISA and the MULTIPLEX platform, respectively. LPO MFI on PBMCs/monocytes were significantly higher in patients (median 4456 and 9091, respectively) compared with HC (1900, p < 0.05, and 4551, p < 0.01, respectively). Patients had higher ferritin expression on PBMCs (mean fold, 1.02) than HC (0.55, p < 0.05). Their ferritin expression levels on PBMCs stimulated with LPO inducers erastin or RSL3 (2.47 or 1.61, respectively) were higher than HC (0.84, p < 0.05, or 0.74, p < 0.01). Ferritin expression on erastin-treated/IL-1β-treated macrophages from patients were higher than those from HC (p < 0.001). The elevated levels of LPO-related metabolites, including malondialdehyde and 4-hydroxyalkenals, were positively correlated with disease activity scores, suggesting LPO involvement in AOSD pathogenesis. Increased ferritin expression on PBMCs/macrophages stimulated with LPO inducers indicates a link between LPO and elevated ferritin. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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10 pages, 1987 KiB

Open AccessArticle

Lobeglitazone Exerts Anti-Inflammatory Effect in Lipopolysaccharide-Induced Bone-Marrow Derived Macrophages

by Dabin Jeong, Wan-Kyu Ko, Seong-Jun Kim, Gong-Ho Han, Daye Lee, Seung-Hun Sheen and Seil Sohn

Biomedicines 2021, 9(10), 1432; https://doi.org/10.3390/biomedicines9101432 - 10 Oct 2021

Cited by 6 | Viewed by 3177

Abstract

The purpose of this study is to elucidate the anti-inflammatory effect of lobeglitazone (LOBE) in lipopolysaccharide (LPS)-induced bone-marrow derived macrophages (BMDMs). We induced nitric oxide (NO) production and pro-inflammatory gene expression through LPS treatment in BMDMs. The changes of NO release and expression [...] Read more.

The purpose of this study is to elucidate the anti-inflammatory effect of lobeglitazone (LOBE) in lipopolysaccharide (LPS)-induced bone-marrow derived macrophages (BMDMs). We induced nitric oxide (NO) production and pro-inflammatory gene expression through LPS treatment in BMDMs. The changes of NO release and expression of pro-inflammatory mediators by LOBE were assessed via NO quantification assay and a real-time quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, the regulatory effect of LOBE on activation of mitogen-activated protein kinase (MAPK) signaling pathway was investigated by measuring the phosphorylation state of extracellular regulatory protein (ERK) and c-Jun N-terminal kinase (JNK) proteins by Western blot. Our results show that LOBE significantly reduced LPS-induced NO production and pro-inflammatory gene expression of interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and monocyte chemoattractant protein-1 (MCP-1). Moreover, LOBE reduced phosphorylation levels of ERK and JNK of MAPK signaling pathway. In conclusion, LOBE exerts an anti-inflammatory effect in LPS-induced BMDMs by suppression of NO production and pro-inflammatory gene expression, and this effect is potentially through inhibition of the MARK signaling pathway. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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23 pages, 5729 KiB

Open AccessArticle

Cell Properties of Lung Tissue-Resident Macrophages Propagated by Co-Culture with Lung Fibroblastic Cells from C57BL/6 and BALB/c Mice

by Mayu Tsurutani, Haruka Horie and Kazushige Ogawa

Biomedicines 2021, 9(9), 1241; https://doi.org/10.3390/biomedicines9091241 - 16 Sep 2021

Cited by 7 | Viewed by 3396

Abstract

Tissue-resident macrophages (Mø) originating from foetal precursors are maintained by self-renewal under tissue/organ-specific microenvironments (niches). We recently developed a simple propagation method applicable to tissue-resident Mø by co-culturing. Here, we examined the properties of lung tissue-resident Mø propagated by co-culturing with lung interstitial [...] Read more.

Tissue-resident macrophages (Mø) originating from foetal precursors are maintained by self-renewal under tissue/organ-specific microenvironments (niches). We recently developed a simple propagation method applicable to tissue-resident Mø by co-culturing. Here, we examined the properties of lung tissue-resident Mø propagated by co-culturing with lung interstitial cells. The intracardially and intratracheally perfused lung from BALB/c and C57BL/6 mice could minimise the contamination of alveolar Mø and lung monocytes. Lung tissue-resident Mø could be largely propagated under standard culture media along with the propagation of lung interstitial cells demonstrating a fibroblastic morphology. Propagated lung Mø showed characteristic expression properties for Mø/monocyte markers: high expressions of CD11b, CD64 and CD206; substantial expressions of Mertk; and negative expressions of Ly6C, MHC II and Siglec-F. These properties fit with those of lung interstitial Mø of a certain population that can undergo self-renewal. Propagated fibroblastic cells by co-culturing with lung Mø possessed niche properties such as Csf1 and Tgfb1 expression. Propagated lung Mø from both the mouse types were polarised to an M2 phenotype highly expressing arginase 1 without M2 inducer treatment, whereas the M1 inducers significantly increased the iNOS-positive cell percentages in C57BL/6 mice relative to those in BALB/c mice. This is the first study to demonstrate fundamental properties of lung tissue-resident Mø propagated by co-culturing. Propagated lung Mø showing features of lung interstitial Mø can serve as an indispensable tool for investigating SARS-CoV-2 diseases, although lung interstitial Mø have gained little attention in terms of their involvement in SARS-CoV-2 disease pathology, in contrast to alveolar and recruited Mø. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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14 pages, 2081 KiB

Open AccessArticle

MARCO⁺ Macrophage Dynamics in Regenerating Liver after 70% Liver Resection in Mice

by Andrey Elchaninov, Anastasia Lokhonina, Polina Vishnyakova, Anna Soboleva, Anastasiya Poltavets, Daria Artemova, Andrey Makarov, Valeria Glinkina, Dmitry Goldshtein, Galina Bolshakova, Gennady Sukhikh and Timur Fatkhudinov

Biomedicines 2021, 9(9), 1129; https://doi.org/10.3390/biomedicines9091129 - 1 Sep 2021

Cited by 10 | Viewed by 3901

Abstract

Background: Macrophages play a key role in liver regeneration. The fates of resident macrophages after 70% resection are poorly investigated. In this work, using the MARCO macrophage marker (abbreviated from macrophage receptor with collagenous structure), we studied the dynamics of mouse liver resident [...] Read more.

Background: Macrophages play a key role in liver regeneration. The fates of resident macrophages after 70% resection are poorly investigated. In this work, using the MARCO macrophage marker (abbreviated from macrophage receptor with collagenous structure), we studied the dynamics of mouse liver resident macrophages after 70% resection. Methods: In BALB/c male mice, a model of liver regeneration after 70% resection was reproduced. The dynamics of markers CD68, TIM4, and MARCO were studied immunohistochemically and by using a Western blot. Results: The number of MARCO- and CD68-positive macrophages in the regenerating liver increased 1 day and 3 days after resection, respectively. At the same time, the content of the MARCO protein increased in the sorted macrophages of the regenerating liver on the third day. Conclusions: The data indicate that the number of MARCO-positive macrophages in the regenerating liver increases due to the activation of MARCO synthesis in the liver macrophages. The increased expression of MARCO by macrophages can be regarded as a sign of their activation. In the present study, stimulation with LPS led to an increase in the expression of the Marco gene in both Kupffer cells and macrophages of bone marrow origin. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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10 pages, 1231 KiB

Open AccessArticle

Glucose-Dependent Insulinotropic Polypeptide Suppresses Foam Cell Formation of Macrophages through Inhibition of the Cyclin-Dependent Kinase 5-CD36 Pathway

by Michishige Terasaki, Hironori Yashima, Yusaku Mori, Tomomi Saito, Yoshie Shiraga, Raichi Kawakami, Makoto Ohara, Tomoyasu Fukui, Tsutomu Hirano, Yuichiro Yamada, Yutaka Seino and Sho-ichi Yamagishi

Biomedicines 2021, 9(7), 832; https://doi.org/10.3390/biomedicines9070832 - 16 Jul 2021

Cited by 10 | Viewed by 2640

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation [...] Read more.

Glucose-dependent insulinotropic polypeptide (GIP) has been reported to have an atheroprotective property in animal models. However, the effect of GIP on macrophage foam cell formation, a crucial step of atherosclerosis, remains largely unknown. We investigated the effects of GIP on foam cell formation of, and CD36 expression in, macrophages extracted from GIP receptor-deficient (Gipr^−/−) and Gipr^+/+ mice and cultured human U937 macrophages by using an agonist for GIP receptor, [D-Ala²]GIP(1–42). Foam cell formation evaluated by esterification of free cholesterol to cholesteryl ester and CD36 gene expression in macrophages isolated from Gipr^+/+ mice infused subcutaneously with [D-Ala²]GIP(1–42) were significantly suppressed compared with vehicle-treated mice, while these beneficial effects were not observed in macrophages isolated from Gipr^−/− mice infused with [D-Ala²]GIP(1–42). When macrophages were isolated from Gipr^+/+ and Gipr^−/− mice, and then exposed to [D-Ala²]GIP(1–42), similar results were obtained. [D-Ala²]GIP(1–42) attenuated ox-LDL uptake of, and CD36 gene expression in, human U937 macrophages as well. Gene expression level of cyclin-dependent kinase 5 (Cdk5) was also suppressed by [D-Ala²]GIP(1–42) in U937 cells, which was corelated with that of CD36. A selective inhibitor of Cdk5, (R)-DRF053 mimicked the effects of [D-Ala²]GIP(1–42) in U937 cells. The present study suggests that GIP could inhibit foam cell formation of macrophages by suppressing the Cdk5-CD36 pathway via GIP receptor. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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20 pages, 2621 KiB

Open AccessArticle

Phenotypic and Functional Heterogeneity of Low-Density and High-Density Human Lung Macrophages

by Barbara Balestrieri, Francescopaolo Granata, Stefania Loffredo, Angelica Petraroli, Giulia Scalia, Paolo Morabito, Chiara Cardamone, Gilda Varricchi and Massimo Triggiani

Biomedicines 2021, 9(5), 505; https://doi.org/10.3390/biomedicines9050505 - 4 May 2021

Cited by 18 | Viewed by 2691

Abstract

Background: Pulmonary macrophages are a highly heterogeneous cell population distributed in different lung compartments. Methods: We separated two subpopulations of macrophages from human lung parenchyma according to flotation over density gradients. Results: Two-thirds 65.4% of the lung macrophages have a density between 1.065 [...] Read more.

Background: Pulmonary macrophages are a highly heterogeneous cell population distributed in different lung compartments. Methods: We separated two subpopulations of macrophages from human lung parenchyma according to flotation over density gradients. Results: Two-thirds 65.4% of the lung macrophages have a density between 1.065 and 1.078 (high-density macrophages: HDMs), and the remaining one-third (34.6) had a density between 1.039 and 1.052 (low-density macrophages: LDMs). LDMs had a larger area (691 vs. 462 μm²) and cell perimeter (94 vs. 77 μm) compared to HDMs. A significantly higher percentage of HDMs expressed CD40, CD45, and CD86 compared to LDMs. In contrast, a higher percentage of LDMs expressed the activation markers CD63 and CD64. The release of TNF-α, IL-6, IL-10 and IL-12 induced by lipopolysaccharide (LPS) was significantly higher in HDMs than in LDMs. Conclusion: The human lung contains two subpopulations of macrophages that differ in buoyancy, morphometric parameters, surface marker expression and response to LPS. These subpopulations of macrophages probably play distinct roles in lung inflammation and immune responses. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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10 pages, 3737 KiB

Open AccessCommunication

The Effects of Macrophage Phenotype on Osteogenic Differentiation of MSCs in the Presence of Polyethylene Particles

by Qi Gao, Claire Rhee, Masahiro Maruyama, Zhong Li, Huaishuang Shen, Ning Zhang, Takeshi Utsunomiya, Elijah Ejun Huang, Zhenyu Yao, Bruce A. Bunnell, Hang Lin, Rocky S. Tuan and Stuart B. Goodman

Biomedicines 2021, 9(5), 499; https://doi.org/10.3390/biomedicines9050499 - 1 May 2021

Cited by 12 | Viewed by 3215

Abstract

Wear debris generated from the bearing surfaces of joint arthroplasties leads to acute and chronic inflammation, which is strongly associated with implant failure. Macrophages derived from monocytes recruited to the local tissues have a significant impact on bone healing and regeneration. Macrophages can [...] Read more.

Wear debris generated from the bearing surfaces of joint arthroplasties leads to acute and chronic inflammation, which is strongly associated with implant failure. Macrophages derived from monocytes recruited to the local tissues have a significant impact on bone healing and regeneration. Macrophages can adopt various functional phenotypes. While M1 macrophages are pro-inflammatory, M2 macrophages express factors important for tissue repair. Here, we established a 3D co-culture system to investigate how the immune system influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in the presence of micron-sized particles. This system allowed for the simulation of an inflammatory reaction via the addition of Lipopolysaccharide-contaminated polyethylene particles (cPE) and the characterization of bone formation using micro-CT and gene and protein expression. Co-cultures of MSCs with M2 macrophages in the presence of cPE in a 3D environment resulted in the increased expression of osteogenic markers, suggesting facilitation of bone formation. In this model, the upregulation of M2 macrophage expression of immune-associated genes and cytokines contributes to enhanced bone formation by MSCs. This study elucidates how the immune system modulates bone healing in response to an inflammatory stimulus using a unique 3D culture system. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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22 pages, 3468 KiB

Open AccessEditor’s ChoiceArticle

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

by Giuseppe Caruso, Cristina Benatti, Nicolò Musso, Claudia G. Fresta, Annamaria Fidilio, Giorgia Spampinato, Nicoletta Brunello, Claudio Bucolo, Filippo Drago, Susan M. Lunte, Blake R. Peterson, Fabio Tascedda and Filippo Caraci

Biomedicines 2021, 9(5), 477; https://doi.org/10.3390/biomedicines9050477 - 26 Apr 2021

Cited by 29 | Viewed by 4373

Abstract

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this [...] Read more.

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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10 pages, 1991 KiB

Open AccessArticle

Enhanced Palmitate-Induced Interleukin-8 Formation in Human Macrophages by Insulin or Prostaglandin E₂

by Janin Henkel, Julia Klauder, Meike Statz, Anne-Sophie Wohlenberg, Sonja Kuipers, Madita Vahrenbrink and Gerhard Paul Püschel

Biomedicines 2021, 9(5), 449; https://doi.org/10.3390/biomedicines9050449 - 21 Apr 2021

Cited by 5 | Viewed by 2357

Abstract

Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E₂ (PGE₂) released [...] Read more.

Macrophages in pathologically expanded dysfunctional white adipose tissue are exposed to a mix of potential modulators of inflammatory response, including fatty acids released from insulin-resistant adipocytes, increased levels of insulin produced to compensate insulin resistance, and prostaglandin E₂ (PGE₂) released from activated macrophages. The current study addressed the question of how palmitate might interact with insulin or PGE₂ to induce the formation of the chemotactic pro-inflammatory cytokine interleukin-8 (IL-8). Human THP-1 cells were differentiated into macrophages. In these macrophages, palmitate induced IL-8 formation. Insulin enhanced the induction of IL-8 formation by palmitate as well as the palmitate-dependent stimulation of PGE₂ synthesis. PGE₂ in turn elicited IL-8 formation on its own and enhanced the induction of IL-8 release by palmitate, most likely by activating the EP4 receptor. Since IL-8 causes insulin resistance and fosters inflammation, the increase in palmitate-induced IL-8 formation that is caused by hyperinsulinemia and locally produced PGE₂ in chronically inflamed adipose tissue might favor disease progression in a vicious feed-forward cycle. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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Review

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16 pages, 2460 KiB

Open AccessReview

Pathological Significance of Macrophages in Erectile Dysfunction Including Peyronie’s Disease

by Yasuyoshi Miyata, Tomohiro Matsuo, Yuichiro Nakamura, Kensuke Mitsunari, Kojiro Ohba and Hideki Sakai

Biomedicines 2021, 9(11), 1658; https://doi.org/10.3390/biomedicines9111658 - 10 Nov 2021

Cited by 8 | Viewed by 3396

Abstract

Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many [...] Read more.

Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many factors, such as fibrosis, lipid metabolism abnormalities, the immune system, and stem cells, play crucial roles in the etiology and development of ED. Although phosphodiesterase type 5 (PDE5) inhibitors are currently the standard treatment agents for patients with ED, they are effective only in a subgroup of patients. Therefore, further insight into the pathological mechanism underlying ED is needed to discuss ED treatment strategies. In this review, we focused on the biological and pathological significance of macrophages in ED because the interaction of macrophages with ED-related mechanisms have not been well explored, despite their important roles in vasculogenic and neurogenic diseases. Furthermore, we examined the pathological significance of macrophages in Peyronie’s disease (PD), a cause of ED characterized by penile deformation (visible curvature) during erection and pain. Although microinjury and the subsequent abnormal healing process of the tunica albuginea are known to be important processes in this disease, the detailed etiology and pathophysiology of PD are not fully understood. This is the first review on the pathological role of macrophages in PD. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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17 pages, 782 KiB

Open AccessReview

Two Faces of Macrophages: Training and Tolerance

by Kiran Zubair, Chaelin You, Geunho Kwon and Kyuho Kang

Biomedicines 2021, 9(11), 1596; https://doi.org/10.3390/biomedicines9111596 - 2 Nov 2021

Cited by 22 | Viewed by 4847

Abstract

Macrophages are present in almost all body tissues. They detect and quickly respond to “environmental signals” in the tissue. Macrophages have been associated with numerous beneficial roles, such as host defense, wound healing, and tissue regeneration; however, they have also been linked to [...] Read more.

Macrophages are present in almost all body tissues. They detect and quickly respond to “environmental signals” in the tissue. Macrophages have been associated with numerous beneficial roles, such as host defense, wound healing, and tissue regeneration; however, they have also been linked to the development of diverse illnesses, particularly cancers and autoimmune disorders. Complex signaling, epigenetic, and metabolic pathways drive macrophage training and tolerance. The induced intracellular program differs depending on the type of initial stimuli and the tissue microenvironment. Due to the essential roles of macrophages in homeostatic and their association with the pathogenesis of inflammatory diseases, recent studies have investigated the molecular mechanisms of macrophage training and tolerance. This review discusses the role of factors involved in macrophage training and tolerance, along with the current studies in human diseases. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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11 pages, 668 KiB

Open AccessReview

Macrophages and Iron: A Special Relationship

by Stefania Recalcati and Gaetano Cairo

Biomedicines 2021, 9(11), 1585; https://doi.org/10.3390/biomedicines9111585 - 30 Oct 2021

Cited by 30 | Viewed by 4758

Abstract

Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages [...] Read more.

Macrophages perform a variety of different biological functions and are known for their essential role in the immune response. In this context, a principal function is phagocytic clearance of pathogens, apoptotic and senescent cells. However, the major targets of homeostatic phagocytosis by macrophages are old/damaged red blood cells. As such, macrophages play a crucial role in iron trafficking, as they recycle the large quantity of iron obtained by hemoglobin degradation. They also seem particularly adapted to handle and store amounts of iron that would be toxic to other cell types. Here, we examine the specific and peculiar iron metabolism of macrophages. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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17 pages, 6323 KiB

Open AccessReview

The Role of Microglia in the Development of Neurodegenerative Diseases

by Jae-Won Lee, Wanjoo Chun, Hee Jae Lee, Seong-Man Kim, Jae-Hong Min, Doo-Young Kim, Mun-Ock Kim, Hyung Won Ryu and Su Ui Lee

Biomedicines 2021, 9(10), 1449; https://doi.org/10.3390/biomedicines9101449 - 12 Oct 2021

Cited by 24 | Viewed by 5077

Abstract

Microglia play an important role in the maintenance and neuroprotection of the central nervous system (CNS) by removing pathogens, damaged neurons, and plaques. Recent observations emphasize that the promotion and development of neurodegenerative diseases (NDs) are closely related to microglial activation. In this [...] Read more.

Microglia play an important role in the maintenance and neuroprotection of the central nervous system (CNS) by removing pathogens, damaged neurons, and plaques. Recent observations emphasize that the promotion and development of neurodegenerative diseases (NDs) are closely related to microglial activation. In this review, we summarize the contribution of microglial activation and its associated mechanisms in NDs, such as epilepsy, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), based on recent observations. This review also briefly introduces experimental animal models of epilepsy, AD, PD, and HD. Thus, this review provides a better understanding of microglial functions in the development of NDs, suggesting that microglial targeting could be an effective therapeutic strategy for these diseases. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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16 pages, 1727 KiB

Open AccessReview

Macrophage Identification In Situ

by Krisztina Nikovics and Anne-Laure Favier

Biomedicines 2021, 9(10), 1393; https://doi.org/10.3390/biomedicines9101393 - 4 Oct 2021

Cited by 12 | Viewed by 3203

Abstract

Understanding the processes of inflammation and tissue regeneration after injury is of great importance. For a long time, macrophages have been known to play a central role during different stages of inflammation and tissue regeneration. However, the molecular and cellular mechanisms by which [...] Read more.

Understanding the processes of inflammation and tissue regeneration after injury is of great importance. For a long time, macrophages have been known to play a central role during different stages of inflammation and tissue regeneration. However, the molecular and cellular mechanisms by which they exert their effects are as yet mostly unknown. While in vitro macrophages have been characterized, recent progress in macrophage biology studies revealed that macrophages in vivo exhibited distinctive features. Actually, the precise characterization of the macrophages in vivo is essential to develop new healing treatments and can be approached via in situ analyses. Nowadays, the characterization of macrophages in situ has improved significantly using antigen surface markers and cytokine secretion identification resulting in specific patterns. This review aims for a comprehensive overview of different tools used for in situ macrophage identification, reporter genes, immunolabeling and in situ hybridization, discussing their advantages and limitations. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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10 pages, 679 KiB

Open AccessReview

Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy

by Sarah Di Somma, Fabiana Napolitano, Giuseppe Portella and Anna Maria Malfitano

Biomedicines 2021, 9(10), 1309; https://doi.org/10.3390/biomedicines9101309 - 24 Sep 2021

Cited by 6 | Viewed by 3075

Abstract

Cellular compartments constituting the tumor microenvironment including immune cells, fibroblasts, endothelial cells, and mesenchymal stromal/stem cells communicate with malignant cells to orchestrate a series of signals that contribute to the evolution of the tumor microenvironment. In this study, we will focus on the [...] Read more.

Cellular compartments constituting the tumor microenvironment including immune cells, fibroblasts, endothelial cells, and mesenchymal stromal/stem cells communicate with malignant cells to orchestrate a series of signals that contribute to the evolution of the tumor microenvironment. In this study, we will focus on the interplay in tumor microenvironment between macrophages and mesenchymal stem cells and macrophages and fibroblasts. In particular, cell–cell interaction and mediators secreted by these cells will be examined to explain pro/anti-tumor phenotypes induced in macrophages. Nonetheless, in the context of virotherapy, the response of macrophages as a consequence of treatment with oncolytic viruses will be analyzed regarding their polarization status and their pro/anti-tumor response. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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13 pages, 1038 KiB

Open AccessReview

Macrophages and Foam Cells: Brief Overview of Their Role, Linkage, and Targeting Potential in Atherosclerosis

by Anastasia V. Poznyak, Nikita G. Nikiforov, Antonina V. Starodubova, Tatyana V. Popkova and Alexander N. Orekhov

Biomedicines 2021, 9(9), 1221; https://doi.org/10.3390/biomedicines9091221 - 14 Sep 2021

Cited by 46 | Viewed by 7020

Abstract

Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the [...] Read more.

Atherosclerosis is still one of the main causes of death around the globe. This condition leads to various life-threatening cardiovascular complications. However, no effective preventive measures are known apart from lifestyle corrections, and no cure has been developed. Despite numerous studies in the field of atherogenesis, there are still huge gaps in already poor understanding of mechanisms that underlie the disease. Inflammation and lipid metabolism violations are undoubtedly the key players, but many other factors, such as oxidative stress, endothelial dysfunction, contribute to the pathogenesis of atherosclerosis. This overview is focusing on the role of macrophages in atherogenesis, which are at the same time a part of the inflammatory response, and also tightly linked to the foam cell formation, thus taking part in both crucial for atherogenesis processes. Being essentially involved in atherosclerosis development, macrophages and foam cells have attracted attention as a promising target for therapeutic approaches. Full article

(This article belongs to the Special Issue Macrophages in Health and Non-infectious Disease 2.0)

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