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Human and Animal Monocytes and Macrophages in Homeostasis and Disease 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 21248

Special Issue Editors


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Guest Editor
Dynamics and Mechanics of Epithelia Group, Faculty of Medicine, Institute of Genetics and Development of Rennes, University of Rennes, CNRS, UMR 6290, 35043 Rennes, France
Interests: embryo development; cell cycle; gene regulation; cancer; stem cells; gonads; genetic diseases
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Transplant Immunology, The Houston Methodist Research Institute, Houston, TX 77030, USA
Interests: macrophages; actin cytoskeleton; RhoA pathway; chronic rejection; transplantation; germ cells; stem cells; Xenopus laevis; development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Monocytes and macrophages play fundamental roles in organisms’ homeostasis and inflammatory processes, in both physiological and pathological situations. Tissue-resident macrophages participate in tissue/organ renewal, and by changing their microbicidal properties, they accommodate organism microbiota. In SARS-CoV-2 infection, monocytes and alveolar macrophages are involved in the development of the acute respiratory distress syndrome (ARDS) through the exacerbated secretion of pro-inflammatory factors. The management of this macrophage-derived cytokine storm is of paramount importance during the current COVID-19 pandemic. Another burning issue in which monocytes and macrophages play important roles is diabetes mellitus and the inflammatory processes involved in its etiology. The specialized subpopulation of macrophages, tumor-associated macrophages (TAMs), plays a role in the development and metastasis of cancer. Monocytes and macrophages are also responsible for the chronic rejection and long-term failure of transplanted organs. The efficient fight against these scourges requires a better understanding of the molecular and cellular mechanisms allowing monocytes and macrophages to underreact or overreact in their homeostatic and/or pathogen fighting roles. For this Special Issue, we invite research and review articles on recent progress in physiology and pathology linked to human and animal monocyte and macrophage functions in homeostasis and diseases.

Prof. Dr. Jacek Z. Kubiak
Prof. Dr. Malgorzata Kloc
Guest Editors

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Keywords

  • monocytes
  • macrophages
  • inflammation
  • diseases
  • COVID-19
  • diabetes mellitus
  • polarity
  • phagocytosis
  • cytokine secretion
  • chemotaxis

Published Papers (12 papers)

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Editorial

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5 pages, 224 KiB  
Editorial
The Role of Human and Animal Monocytes and Macrophages in Homeostasis and Disease
by Malgorzata Kloc and Jacek Z. Kubiak
Int. J. Mol. Sci. 2023, 24(22), 16397; https://doi.org/10.3390/ijms242216397 - 16 Nov 2023
Viewed by 650
Abstract
Monocytes and macrophages are the innate immune cells that are the first-line responders to invading pathogens or foreign objects[...] Full article

Research

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18 pages, 12698 KiB  
Article
Macrophages Provide Essential Support for Erythropoiesis, and Extracellular ATP Contributes to a Erythropoiesis-Supportive Microenvironment during Repeated Psychological Stress
by Sanja Momčilović, Andrija Bogdanović, Maja S. Milošević, Slavko Mojsilović, Dragana C. Marković, Dušica M. Kočović and Sanja Vignjević Petrinović
Int. J. Mol. Sci. 2023, 24(14), 11373; https://doi.org/10.3390/ijms241411373 - 12 Jul 2023
Cited by 1 | Viewed by 970
Abstract
Psychological stress is a significant contributor to various chronic diseases and affects multiple physiological processes including erythropoiesis. This study aimed to examine the tissue-specific contributions of macrophages and extracellular ATP, as a signal of disturbed tissue homeostasis, to erythropoiesis under conditions of repeated [...] Read more.
Psychological stress is a significant contributor to various chronic diseases and affects multiple physiological processes including erythropoiesis. This study aimed to examine the tissue-specific contributions of macrophages and extracellular ATP, as a signal of disturbed tissue homeostasis, to erythropoiesis under conditions of repeated psychological stress. Adult male BALB/c mice were subjected to 2 h daily restraint stress for seven consecutive days. Clodronate-liposomes were used to deplete resident macrophages from the bone marrow and spleen two days prior to the first restraint procedure, as well as newly recruited macrophages, every third day for the duration of the experiment. Repeated stress induced a considerable increase in the number of erythroid progenitor cells as well as in the percentage of CD71+/Ter119+ and CD71−/Ter119+ cells in the bone marrow and spleen. Macrophage depletion completely abolished the stimulative effect of repeated stress on immature erythroid cells, and prevented stress-induced increases in ATP levels, P2X7 receptor (P2X7R) expression, and ectonucleotidase CD39 activity and expression in the bone marrow and spleen. The obtained results demonstrate the stimulative effects of repeated stress on erythroid cells, extracellular ATP levels, P2X7R expression, CD39 activity and expression within the bone marrow and spleen, as well as the essential role of macrophages in stress-induced changes. Full article
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17 pages, 5382 KiB  
Article
A2BAR Antagonism Decreases the Glomerular Expression and Secretion of Chemoattractants for Monocytes and the Pro-Fibrotic M2 Macrophages Polarization during Diabetic Nephropathy
by Ángelo Torres-Arévalo, Yéssica Nahuelpán, Katherin Muñoz, Claudia Jara, Claudio Cappelli, Agnieszka Taracha-Wiśniewska, Claudia Quezada-Monrás and Rody San Martín
Int. J. Mol. Sci. 2023, 24(13), 10829; https://doi.org/10.3390/ijms241310829 - 29 Jun 2023
Cited by 1 | Viewed by 1348
Abstract
Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and [...] Read more.
Some chemoattractants and leukocytes such as M1 and M2 macrophages are known to be involved in the development of glomerulosclerosis during diabetic nephropathy (DN). In the course of diabetes, an altered and defective cellular metabolism leads to the increase in adenosine levels, and thus to changes in the polarity (M1/M2) of macrophages. MRS1754, a selective antagonist of the A2B adenosine receptor (A2BAR), attenuated glomerulosclerosis and decreased macrophage-myofibroblast transition in DN rats. Therefore, we aimed to investigate the effect of MRS1754 on the glomerular expression/secretion of chemoattractants, the intraglomerular infiltration of leukocytes, and macrophage polarity in DN rats. Kidneys/glomeruli of non-diabetic, DN, and MRS1754-treated DN rats were processed for transcriptomic analysis, immunohistopathology, ELISA, and in vitro macrophage migration assays. The transcriptomic analysis identified an upregulation of transcripts and pathways related to the immune system in the glomeruli of DN rats, which was attenuated using MRS1754. The antagonism of the A2BAR decreased glomerular expression/secretion of chemoattractants (CCL2, CCL3, CCL6, and CCL21), the infiltration of macrophages, and their polarization to M2 in DN rats. The in vitro macrophages migration induced by conditioned-medium of DN glomeruli was significantly decreased using neutralizing antibodies against CCL2, CCL3, and CCL21. We concluded that the pharmacological blockade of the A2BAR decreases the transcriptional expression of genes/pathways related to the immune response, protein expression/secretion of chemoattractants, as well as the infiltration of macrophages and their polarization toward the M2 phenotype in the glomeruli of DN rats, suggesting a new mechanism implicated in the antifibrotic effect of MRS1754. Full article
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20 pages, 3664 KiB  
Article
Uremic Toxin Indoxyl Sulfate Promotes Macrophage-Associated Low-Grade Inflammation and Epithelial Cell Senescence
by Andrea Ribeiro, Feiyue Liu, Matthias Srebrzynski, Simone Rother, Karina Adamowicz, Marta Wadowska, Stefanie Steiger, Hans-Joachim Anders, Christoph Schmaderer, Joanna Koziel and Maciej Lech
Int. J. Mol. Sci. 2023, 24(9), 8031; https://doi.org/10.3390/ijms24098031 - 28 Apr 2023
Cited by 3 | Viewed by 1549
Abstract
In this study, we investigated the impact of the uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells and its role in modulating the response to lipopolysaccharide (LPS). Indoxyl sulfate accumulates in the blood of patients with chronic kidney disease (CKD) and [...] Read more.
In this study, we investigated the impact of the uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells and its role in modulating the response to lipopolysaccharide (LPS). Indoxyl sulfate accumulates in the blood of patients with chronic kidney disease (CKD) and is a predictor of overall and cardiovascular morbidity/mortality. To simulate the uremic condition, primary macrophages and tubular epithelial cells were incubated with indoxyl sulfate at low concentrations as well as concentrations found in uremic patients, both alone and upon LPS challenge. The results showed that indoxyl sulfate alone induced the release of reactive oxygen species and low-grade inflammation in macrophages. Moreover, combined with LPS (proinflammatory conditions), indoxyl sulfate significantly increased TNF-α, CCL2, and IL-10 release but did not significantly affect the polarization of macrophages. Pre-treatment with indoxyl sulfate following LPS challenge induced the expression of aryl hydrocarbon receptor (Ahr) and NADPH oxidase 4 (Nox4) which generate reactive oxygen species (ROS). Further, experiments with tubular epithelial cells revealed that indoxyl sulfate might induce senescence in parenchymal cells and therefore participate in the progression of inflammaging. In conclusion, this study provides evidence that indoxyl sulfate provokes low-grade inflammation, modulates macrophage function, and enhances the inflammatory response associated with LPS. Finally, indoxyl sulfate signaling contributes to the senescence of tubular epithelial cells during injury. Full article
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14 pages, 7567 KiB  
Article
Interleukin 26 Induces Macrophage IL-9 Expression in Rheumatoid Arthritis
by Yi-Hsun Wang, Yi-Jen Peng, Feng-Cheng Liu, Gu-Jiun Lin, Shing-Hwa Huang, Huey-Kang Sytwu and Chia-Pi Cheng
Int. J. Mol. Sci. 2023, 24(8), 7526; https://doi.org/10.3390/ijms24087526 - 19 Apr 2023
Viewed by 1479
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease with chronic inflammation, bone erosion, and joint deformation. Synovial tissue in RA patients is full of proinflammatory cytokines and infiltrated immune cells, such as T help (Th) 9, Th17, macrophages, and osteoclasts. Recent reports emphasized a [...] Read more.
Rheumatoid arthritis (RA) is an autoimmune disease with chronic inflammation, bone erosion, and joint deformation. Synovial tissue in RA patients is full of proinflammatory cytokines and infiltrated immune cells, such as T help (Th) 9, Th17, macrophages, and osteoclasts. Recent reports emphasized a new member of the interleukin (IL)-10 family, IL-26, an inducer of IL-17A that is overexpressed in RA patients. Our previous works found that IL-26 inhibits osteoclastogenesis and conducts monocyte differentiation toward M1 macrophages. In this study, we aimed to clarify the effect of IL-26 on macrophages linking to Th9 and Th17 in IL-9 and IL-17 expression and downstream signal transduction. Murine and human macrophage cell lines and primary culture cells were used and stimulated by IL26. Cytokines expressions were evaluated by flow cytometry. Signal transduction and transcription factors expression were detected by Western blot and real time-PCR. Our results show that IL-26 and IL-9 colocalized in macrophage in RA synovium. IL-26 directly induces macrophage inflammatory cytokines IL-9 and IL-17A expression. IL-26 increases the IL-9 and IL-17A upstream mechanisms IRF4 and RelB expression. Moreover, the AKT-FoxO1 pathway is also activated by IL-26 in IL-9 and IL-17A expressing macrophage. Blockage of AKT phosphorylation enhances IL-26 stimulating IL-9-producing macrophage cells. In conclusion, our results support that IL-26 promotes IL-9- and IL-17-expressing macrophage and might initiate IL-9- and IL-17-related adaptive immunity in rheumatoid arthritis. Targeting IL-26 may a potential therapeutic strategy for rheumatoid arthritis or other IL-9 plus IL-17 dominant diseases. Full article
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23 pages, 7288 KiB  
Article
Synthesis of Carvone Derivatives and In Silico and In Vitro Screening of Anti-Inflammatory Activity in Murine Macrophages
by Gabriela Moço, Cátia Sousa, Ana Capitão, Stephen Scott MacKinnon, Alcino Jorge Leitão and Alexandrina Ferreira Mendes
Int. J. Mol. Sci. 2023, 24(3), 2263; https://doi.org/10.3390/ijms24032263 - 23 Jan 2023
Viewed by 2242
Abstract
The chemical modification of natural compounds is a promising strategy to improve their frequently poor bioavailability and low potency. This study aimed at synthesizing chemical derivatives of carvone, a natural monoterpene with anti-inflammatory properties, which we recently identified, and evaluating their potential anti-inflammatory [...] Read more.
The chemical modification of natural compounds is a promising strategy to improve their frequently poor bioavailability and low potency. This study aimed at synthesizing chemical derivatives of carvone, a natural monoterpene with anti-inflammatory properties, which we recently identified, and evaluating their potential anti-inflammatory activity. Fourteen chemical derivatives of carvone were synthesized, purified and their chemical structures confirmed. Noncytotoxic concentrations of the test compounds were selected based on the resazurin reduction assay. Among the tested compounds, four significantly reduced the lipopolysaccharides-induced protein levels of the inducible isoform of the nitric oxide synthase and nitric oxide production and showed a dual effect on pro-IL-1 protein levels in the Raw 264.7 cell line. The Ligand Express drug discovery platform was used to predict the targets of the test compounds, and an enrichment analysis was performed to group the different biological processes and molecular and cellular functions of the tested compounds. Moreover, Ligand Express also predicted that all chemicals evaluated have intestinal and blood–brain barrier permeability, do not inhibit P-gp and do not interact with major receptors. Although presenting anti-inflammatory and some advantageous ADME properties, the tested compounds still have low potency and specificity but may provide novel structures the further chemical modification of which may yield more promising drugs. Full article
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20 pages, 4397 KiB  
Article
Lipopolysaccharide Tolerance Enhances Murine Norovirus Reactivation: An Impact of Macrophages Mainly Evaluated by Proteomic Analysis
by Jiradej Makjaroen, Pornpimol Phuengmaung, Wilasinee Saisorn, Suwasin Udomkarnjananun, Trairak Pisitkun and Asada Leelahavanichkul
Int. J. Mol. Sci. 2023, 24(3), 1829; https://doi.org/10.3390/ijms24031829 - 17 Jan 2023
Cited by 2 | Viewed by 1520
Abstract
Because of endotoxemia during sepsis (a severe life-threatening infection), lipopolysaccharide (LPS) tolerance (the reduced responses to the repeated LPS stimulation) might be one of the causes of sepsis-induced immune exhaustion (the increased susceptibility to secondary infection and/or viral reactivation). In LPS tolerance macrophage [...] Read more.
Because of endotoxemia during sepsis (a severe life-threatening infection), lipopolysaccharide (LPS) tolerance (the reduced responses to the repeated LPS stimulation) might be one of the causes of sepsis-induced immune exhaustion (the increased susceptibility to secondary infection and/or viral reactivation). In LPS tolerance macrophage (twice-stimulated LPS, LPS/LPS) compared with a single LPS stimulation (N/LPS), there was (i) reduced energy of the cell in both glycolysis and mitochondrial activities (extracellular flux analysis), (ii) decreased abundance of the following proteins (proteomic analysis): (a) complex I and II of the mitochondrial electron transport chain, (b) most of the glycolysis enzymes, (c) anti-viral responses with Myxovirus resistance protein 1 (Mx1) and Ubiquitin-like protein ISG15 (Isg15), (d) antigen presentation pathways, and (iii) the down-regulated anti-viral genes, such as Mx1 and Isg15 (polymerase chain reaction). To test the correlation between LPS tolerance and viral reactivation, asymptomatic mice with and without murine norovirus (MNV) infection as determined in feces were tested. In MNV-positive mice, MNV abundance in the cecum, but not in feces, of LPS/LPS mice was higher than that in N/LPS and control groups, while MNV abundance of N/LPS and control were similar. Additionally, the down-regulated Mx1 and Isg15 were also demonstrated in the cecum, liver, and spleen in LPS/LPS-activated mice, regardless of MNV infection, while N/LPS more prominently upregulated these genes in the cecum of MNV-positive mice compared with the MNV-negative group. In conclusion, defects in anti-viral responses after LPS tolerance, perhaps through the reduced energy status of macrophages, might partly be responsible for the viral reactivation. More studies on patients are of interest. Full article
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Review

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12 pages, 1225 KiB  
Review
Macrophage Function Modulated by tPA Signaling in Mouse Experimental Kidney Disease Models
by Ling Lin and Kebin Hu
Int. J. Mol. Sci. 2023, 24(13), 11067; https://doi.org/10.3390/ijms241311067 - 04 Jul 2023
Cited by 1 | Viewed by 1044
Abstract
Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular [...] Read more.
Macrophage infiltration and accumulation is a hallmark of chronic kidney disease. Tissue plasminogen activator (tPA) is a serine protease regulating the homeostasis of blood coagulation, fibrinolysis, and matrix degradation, and has been shown to act as a cytokine to trigger various receptor-mediated intracellular signal pathways, modulating macrophage function in response to kidney injury. In this review, we discuss the current understanding of tPA-modulated macrophage function and underlying signaling mechanisms during kidney fibrosis and inflammation. Full article
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19 pages, 2543 KiB  
Review
Biologic Mechanisms of Macrophage Phenotypes Responding to Infection and the Novel Therapies to Moderate Inflammation
by Renhao Ni, Lingjing Jiang, Chaohai Zhang, Mujie Liu, Yang Luo, Zeming Hu, Xianbo Mou and Yabin Zhu
Int. J. Mol. Sci. 2023, 24(9), 8358; https://doi.org/10.3390/ijms24098358 - 06 May 2023
Cited by 3 | Viewed by 2116
Abstract
Pro-inflammatory and anti-inflammatory types are the main phenotypes of the macrophage, which are commonly notified as M1 and M2, respectively. The alteration of macrophage phenotypes and the progression of inflammation are intimately associated; both phenotypes usually coexist throughout the whole inflammation stage, involving [...] Read more.
Pro-inflammatory and anti-inflammatory types are the main phenotypes of the macrophage, which are commonly notified as M1 and M2, respectively. The alteration of macrophage phenotypes and the progression of inflammation are intimately associated; both phenotypes usually coexist throughout the whole inflammation stage, involving the transduction of intracellular signals and the secretion of extracellular cytokines. This paper aims to address the interaction of macrophages and surrounding cells and tissues with inflammation-related diseases and clarify the crosstalk of signal pathways relevant to the phenotypic metamorphosis of macrophages. On these bases, some novel therapeutic methods are proposed for regulating inflammation through monitoring the transition of macrophage phenotypes so as to prevent the negative effects of antibiotic drugs utilized in the long term in the clinic. This information will be quite beneficial for the diagnosis and treatment of inflammation-related diseases like pneumonia and other disorders involving macrophages. Full article
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12 pages, 1003 KiB  
Review
Memory Macrophages
by Malgorzata Kloc, Jacek Z. Kubiak, Robert Zdanowski and Rafik M. Ghobrial
Int. J. Mol. Sci. 2023, 24(1), 38; https://doi.org/10.3390/ijms24010038 - 20 Dec 2022
Cited by 4 | Viewed by 2057
Abstract
Immunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens [...] Read more.
Immunological memory is a crucial part of the immune defense that allows organisms to respond against previously encountered pathogens or other harmful factors. Immunological memory is based on the establishment of epigenetic modifications of the genome. The ability to memorize encounters with pathogens and other harmful factors and mount enhanced defense upon subsequent encounters is an evolutionarily ancient mechanism operating in all animals and plants. However, the term immunological memory is usually restricted to the organisms (invertebrates and vertebrates) possessing the immune system. The mammalian immune system, with innate and adaptive branches, is the most sophisticated among vertebrates. The concept of innate memory and memory macrophages is relatively new and thus understudied. We introduce the concept of immunological memory and describe types of memory in different species and their evolutionary status. We discuss why the traditional view of innate immune cells as the first-line defenders is too restrictive and how the innate immune cells can accumulate and retain immunologic memory. We describe how the initial priming leads to chromatin remodeling and epigenetic changes, which allow memory macrophage formation. We also summarize what is currently known about the mechanisms underlying development of memory macrophages; their molecular and metabolic signature and surface markers; and how they may contribute to immune defense, diseases, and organ transplantation. Full article
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13 pages, 1396 KiB  
Review
Macrophage-, Dendritic-, Smooth Muscle-, Endothelium-, and Stem Cells-Derived Foam Cells in Atherosclerosis
by Malgorzata Kloc, Jacek Z. Kubiak and Rafik M. Ghobrial
Int. J. Mol. Sci. 2022, 23(22), 14154; https://doi.org/10.3390/ijms232214154 - 16 Nov 2022
Cited by 4 | Viewed by 2598
Abstract
Atherosclerosis is an inflammatory disease depending on the buildup, called plaque, of lipoproteins, cholesterol, extracellular matrix elements, and various types of immune and non-immune cells on the artery walls. Plaque development and growth lead to the narrowing of the blood vessel lumen, blocking [...] Read more.
Atherosclerosis is an inflammatory disease depending on the buildup, called plaque, of lipoproteins, cholesterol, extracellular matrix elements, and various types of immune and non-immune cells on the artery walls. Plaque development and growth lead to the narrowing of the blood vessel lumen, blocking blood flow, and eventually may lead to plaque burst and a blood clot. The prominent cellular components of atherosclerotic plaque are the foam cells, which, by trying to remove lipoprotein and cholesterol surplus, also participate in plaque development and rupture. Although the common knowledge is that the foam cells derive from macrophages, studies of the last decade clearly showed that macrophages are not the only cells able to form foam cells in atherosclerotic plaque. These findings give a new perspective on atherosclerotic plaque formation and composition and define new targets for anti-foam cell therapies for atherosclerosis prevention. This review gives a concise description of foam cells of different pedigrees and describes the main mechanisms participating in their formation and function. Full article
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19 pages, 2416 KiB  
Review
Gut Barrier Damage and Gut Translocation of Pathogen Molecules in Lupus, an Impact of Innate Immunity (Macrophages and Neutrophils) in Autoimmune Disease
by Awirut Charoensappakit, Kritsanawan Sae-khow and Asada Leelahavanichkul
Int. J. Mol. Sci. 2022, 23(15), 8223; https://doi.org/10.3390/ijms23158223 - 26 Jul 2022
Cited by 20 | Viewed by 2780
Abstract
The gut barrier is a single cell layer that separates gut micro-organisms from the host, and gut permeability defects result in the translocation of microbial molecules from the gut into the blood. Despite the silent clinical manifestation, gut translocation of microbial molecules can [...] Read more.
The gut barrier is a single cell layer that separates gut micro-organisms from the host, and gut permeability defects result in the translocation of microbial molecules from the gut into the blood. Despite the silent clinical manifestation, gut translocation of microbial molecules can induce systemic inflammation that might be an endogenous exacerbating factor of systemic lupus erythematosus. In contrast, circulatory immune-complex deposition and the effect of medications on the gut, an organ with an extremely large surface area, of patients with active lupus might cause gut translocation of microbial molecules, which worsens lupus severity. Likewise, the imbalance of gut microbiota may initiate lupus and/or interfere with gut integrity which results in microbial translocation and lupus exacerbation. Moreover, immune hyper-responsiveness of innate immune cells (macrophages and neutrophils) is demonstrated in a lupus model from the loss of inhibitory Fc gamma receptor IIb (FcgRIIb), which induces prominent responses through the cross-link between activating-FcgRs and innate immune receptors. The immune hyper-responsiveness can cause cell death, especially apoptosis and neutrophil extracellular traps (NETosis), which possibly exacerbates lupus, partly through the enhanced exposure of the self-antigens. Leaky gut monitoring and treatments (such as probiotics) might be beneficial in lupus. Here, we discuss the current information on leaky gut in lupus. Full article
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