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In Honor of Elie Metchnikoff, a Nobel Prize Winner, Who Discovered Macrophages as Phagocyte Cells Involved in the Process of Innate Immunity

Special Issue Editor

Special Issue Information

Dear Colleagues,

This Special Issue honors the discoverer of macrophages, Elie Metchnikoff, who observed these phagocytic cells in the process of innate immunity in 1882. Macrophages, which are formed from hematological progenitor cells (from yolk sac, fetal liver and bone marrow hematopoiesis), circulate in the blood and can migrate into tissues, are ubiquitous and differentially regulated in their function by tissue-specific and immunological transcription processes. Due to their versatile functions, several classes are known from which two main subtypes can be distinguished. M1 macrophages, which are typically activated via bacterial lipopolysaccharides and Th1 cytokines (interferons g+a), produce pro-inflammatory cytokines (interleukins IL-1/6/12/23, TNF-a), reactive oxygen (ROS) and nitrogen species (RNS), express the CC chemokine receptors CCR1/5 and are involved in the promotion of T-helper cells (Th1/17). M2 macrophages are anti-inflammatory, are activated via the Th2 cytokines IL-4/13 and produce the cytokines IL-10, tissue growth factor TGF-beta, chemokines (CCL17/18/22/24) and scavenger receptors (CD163, Stabilin-1). Macrophages serve important functions in immune response, development, tissue homeostasis e.g. wound healing and tissue repair. Activated fibroblasts are also directly involved in the recruitment of macrophages. The process of chemotaxis and migration of monocytes e.g. to the site of infection or injury occurs through the secretion of the chemokine monocyte chemoattractant protein-1 (MCP-1) that binds to the CC chemokine receptor 2 (CCR2) on the monocytes. After infection, the pro-inflammatory M1 phenotype of the macrophages is characteristic, leading to the fight against the invasive organisms through the production of ROS, RNS and TH1/17 cells. But it is precisely here that microorganisms show their ability to circumvent the immune response by influencing macrophage polarization and suppressing important functions such as phagocytic activity. But also the pro-inflammatory phenotype itself has to be switched off later because of the collateral tissue destruction. This occurs through apoptosis, or the re-polarization of macrophages into the anti-inflammatory phenotype. But these important functions of the macrophages can be disturbed in chronic diseases and autoimmune diseases, which includes atherosclerosis, asthma, fibrosis, inflammatory bowel disease, rheumatoid arthritis (RA), experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), autoimmune hepatitis, Crohn's disease and chronic demyelinating diseases of the central nervous system. The pathogenesis of these diseases is based on changes in the differentiation, polarization, re-polarization and activation of macrophages. In order to gain a better understanding of how novel therapies can be developed, the diversity of macrophage functions needs to be better understood.

Dr. Pierre Tennstedt
Guest Editor

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Keywords

  • macrophages
  • monocytes
  • phagocytes
  • fibroblast
  • cytokines
  • chronic disease
  • autoimmune disease
  • inflammatory disease
  • immune response
  • disease treatment

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Published Papers (3 papers)

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Research

13 pages, 2301 KiB  
Article
The mRNA-Binding Protein KSRP Limits the Inflammatory Response of Macrophages
by Vanessa Bolduan, Kim-Alicia Palzer, Christoph Hieber, Jenny Schunke, Michael Fichter, Paul Schneider, Stephan Grabbe, Andrea Pautz and Matthias Bros
Int. J. Mol. Sci. 2024, 25(7), 3884; https://doi.org/10.3390/ijms25073884 - 30 Mar 2024
Cited by 2 | Viewed by 1387
Abstract
KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the 3′-untranslated region of mRNA species, which in many cases encode dynamically regulated proteins like cytokines. In the present study, we [...] Read more.
KH-type splicing regulatory protein (KSRP) is a single-stranded nucleic acid-binding protein with multiple functions. It is known to bind AU-rich motifs within the 3′-untranslated region of mRNA species, which in many cases encode dynamically regulated proteins like cytokines. In the present study, we investigated the role of KSRP for the immunophenotype of macrophages using bone marrow-derived macrophages (BMDM) from wild-type (WT) and KSRP−/− mice. RNA sequencing revealed that KSRP−/− BMDM displayed significantly higher mRNA expression levels of genes involved in inflammatory and immune responses, particularly type I interferon responses, following LPS stimulation. In line, time kinetics studies revealed increased levels of interferon-γ (IFN-γ), interleukin (IL)-1β and IL-6 mRNA in KSRP−/− macrophages after 6 h subsequent to LPS stimulation as compared to WT cultures. At the protein level, KSRP−/− BMDM displayed higher levels of these cytokines after overnight stimulation. Matching results were observed for primary peritoneal macrophages of KSRP−/− mice. These showed higher IL-6, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 1 (CXCL1) and CC-chemokine ligand 5 (CCL5) protein levels in response to LPS stimulation than the WT controls. As macrophages play a key role in sepsis, the in vivo relevance of KSRP deficiency for cytokine/chemokine production was analyzed in an acute inflammation model. In agreement with our in vitro findings, KSRP-deficient animals showed higher cytokine production upon LPS administration in comparison to WT mice. Taken together, these findings demonstrate that KSRP constitutes an important negative regulator of cytokine expression in macrophages. Full article
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19 pages, 3868 KiB  
Article
Investigating the Effects of Sex Hormones on Macrophage Polarization
by Sophie Enright and Geoff H. Werstuck
Int. J. Mol. Sci. 2024, 25(2), 951; https://doi.org/10.3390/ijms25020951 - 12 Jan 2024
Cited by 1 | Viewed by 1936
Abstract
Sex differences in the development and progression of cardiovascular disease are well established, but the effects of sex hormones on macrophage polarization and pro-atherogenic functions are not well described. We hypothesize that sex hormones directly modulate macrophage polarization, and thereby regulate the progression [...] Read more.
Sex differences in the development and progression of cardiovascular disease are well established, but the effects of sex hormones on macrophage polarization and pro-atherogenic functions are not well described. We hypothesize that sex hormones directly modulate macrophage polarization, and thereby regulate the progression of atherosclerosis. Bone marrow-derived monocytes from adult male and female C57BL/6 mice were differentiated into macrophages using macrophage colony-stimulating factor (20 ng/mL) and pre-treated with either 17β-estradiol (100 nM), testosterone (100 nM), or a vehicle control for 24 h. Macrophages were polarized into pro- or anti-inflammatory phenotypes and the effects of sex hormone supplementation on the gene expression of macrophage phenotypic markers were assessed using RT-qPCR. Inflammatory markers, including IL-1β, were quantified using an addressable laser bead immunoassay. A transwell migration assay was used to determine changes in macrophage migration. Sex differences were observed in macrophage polarization, inflammatory responses, and migration. Pre-treatment with 17β-estradiol significantly impaired the gene expression of inflammatory markers and the production of IL-1β in inflammatory macrophages. In anti-inflammatory macrophages, 17β-estradiol significantly upregulated the expression of anti-inflammatory markers and enhanced migration. Pre-treatment with testosterone enhanced anti-inflammatory mRNA expression and impaired the production of IL-1β. Our observations suggest a protective role of 17β-estradiol in atherogenesis that may contribute to the sexual dimorphisms in cardiovascular disease observed in human patients. Full article
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15 pages, 3093 KiB  
Article
Polarization of Melatonin-Modulated Colostrum Macrophages in the Presence of Breast Tumor Cell Lines
by Kenia Maria Rezende Silva, Danielle Cristina Honório França, Adriele Ataídes de Queiroz, Danny Laura Gomes Fagundes-Triches, Patrícia Gelli Feres de Marchi, Tassiane Cristina Morais, Adenilda Cristina Honorio-França and Eduardo Luzía França
Int. J. Mol. Sci. 2023, 24(15), 12400; https://doi.org/10.3390/ijms241512400 - 3 Aug 2023
Cited by 2 | Viewed by 1449
Abstract
Human colostrum and milk contain diverse cells and soluble components that have the potential to act against tumors. In breast cancer, macrophages play a significant role in immune infiltration and contribute to the progression and spread of tumors. However, studies suggest that these [...] Read more.
Human colostrum and milk contain diverse cells and soluble components that have the potential to act against tumors. In breast cancer, macrophages play a significant role in immune infiltration and contribute to the progression and spread of tumors. However, studies suggest that these cells can be reprogrammed to act as an antitumor immune response. This study aimed to evaluate the levels of melatonin and its receptors, MT1 (melatonin receptor 1) and MT2 (melatonin receptor 2), in colostrum and assess the differentiation and polarization of the colostrum macrophages modulated by melatonin in the presence of breast tumor cells. Colostrum samples were collected from 116 mothers and tested for their melatonin and receptor levels. The colostrum cells were treated with or without melatonin and then cultured for 24 h in the presence or absence of breast tumor cells. The results showed that melatonin treatment increased the expression of MT1 and MT2 in the colostrum cells. Furthermore, melatonin treatment increased the percentage of M1 macrophages and decreased the percentage of M2 macrophages. When the colostrum macrophages were cocultured with breast tumor cells, melatonin reduced the percentage of both macrophage phenotypes and the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8). These data suggest that melatonin can regulate the inflammatory process via M1 macrophages in the tumor microenvironment and, simultaneously, the progression of M2 macrophages that favor tumorigenesis. Full article
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