scholarly journals SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Mohamed Luban Sobah ◽  
Clifford Liongue ◽  
Alister C. Ward
Keyword(s):  
Immune Cell ◽  
Inflammatory Diseases ◽  
Feedback Regulation ◽  
Cytokine Signaling ◽  
Negative Feedback Regulation ◽  
Autoimmune Conditions ◽  
Socs Proteins ◽  
Ifn Γ ◽  
And Function ◽  
Immune Defects

Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.

scholarly journals Staphylococcal Enterotoxin B-Induced MicroRNA-155 Targets SOCS1 To Promote Acute Inflammatory Lung Injury

2014 ◽  
Vol 82 (7) ◽  
pp. 2971-2979 ◽  
Author(s):  
Roshni Rao ◽  
Prakash Nagarkatti ◽  
Mitzi Nagarkatti
Keyword(s):  
Lung Injury ◽  
Immune Cell ◽  
Tissue Injury ◽  
Staphylococcal Enterotoxin ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Staphylococcal Enterotoxin B ◽  
Functional Link ◽  
Ifn Γ ◽  
Enterotoxin B

ABSTRACTStaphylococcal enterotoxin B (SEB) causes food poisoning in humans. It is considered a biological weapon, and inhalation can trigger lung injury and sometimes respiratory failure. Being a superantigen, SEB initiates an exaggerated inflammatory response. While the role of microRNAs (miRNAs) in immune cell activation is getting increasing recognition, their role in the regulation of inflammatory disease induced by SEB has not been studied. In this investigation, we demonstrate that exposure to SEB by inhalation results in acute inflammatory lung injury accompanied by an altered miRNA expression profile in lung-infiltrating cells. Among the miRNAs that were significantly elevated, miR-155 was the most overexpressed. Interestingly, miR-155−/−mice were protected from SEB-mediated inflammation and lung injury. Further studies revealed a functional link between SEB-induced miR-155 and proinflammatory cytokine gamma interferon (IFN-γ). Through the use of bioinformatics tools, suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ, was identified as a potential target of miR-155. While miR-155−/−mice displayed increased expression ofSocs1, the overexpression of miR-155 led to its suppression, thereby enhancing IFN-γ levels. Additionally, the inhibition of miR-155 resulted in restoredSocs1expression. Together, our data demonstrate an important role for miR-155 in promoting SEB-mediated inflammation in the lungs throughSocs1suppression and suggest that miR-155 may be an important target in preventing SEB-mediated inflammation and tissue injury.

scholarly journals The macrophage IRF8/IRF1 regulome is required for protection against infections and is associated with chronic inflammation

2016 ◽  
Vol 213 (4) ◽  
pp. 585-603 ◽  
Author(s):  
David Langlais ◽  
Luis B. Barreiro ◽  
Philippe Gros
Keyword(s):  
Pulmonary Tuberculosis ◽  
Mouse Models ◽  
Chromatin Immunoprecipitation ◽  
Inflammatory Diseases ◽  
Transcriptional Regulators ◽  
Interferon Γ ◽  
Wild Type ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Ifn Γ ◽  
And Function

IRF8 and IRF1 are transcriptional regulators that play critical roles in the development and function of myeloid cells, including activation of macrophages by proinflammatory signals such as interferon-γ (IFN-γ). Loss of IRF8 or IRF1 function causes severe susceptibility to infections in mice and in humans. We used chromatin immunoprecipitation sequencing and RNA sequencing in wild type and in IRF8 and IRF1 mutant primary macrophages to systematically catalog all of the genes bound by (cistromes) and transcriptionally activated by (regulomes) IRF8, IRF1, PU.1, and STAT1, including modulation of epigenetic histone marks. Of the seven binding combinations identified, two (cluster 1 [IRF8/IRF1/STAT1/PU.1] and cluster 5 [IRF1/STAT1/PU.1]) were found to have a major role in controlling macrophage transcriptional programs both at the basal level and after IFN-γ activation. They direct the expression of a set of genes, the IRF8/IRF1 regulome, that play critical roles in host inflammatory and antimicrobial defenses in mouse models of neuroinflammation and of pulmonary tuberculosis, respectively. In addition, this IRF8/IRF1 regulome is enriched for genes mutated in human primary immunodeficiencies and with loci associated with several inflammatory diseases in humans.

scholarly journals IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation

2020 ◽  
Author(s):  
Fan Zhang ◽  
Joseph R. Mears ◽  
Lorien Shakib ◽  
Jessica I. Beynor ◽  
Sara Shanaj ◽  
...  
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Inflammatory Diseases ◽  
Macrophage Phenotype ◽  
Tnf Α ◽  
Key Driver ◽  
Ifn Γ ◽  
Immunomodulatory Therapies ◽  
Disease Analysis ◽  
Inflammatory Macrophage

AbstractImmunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that an FCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that a CXCL10+ CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such as GBP1, STAT1, and IL1B. We found that the CXCL10+ CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF-α and IFN-γ ex vivo. Our findings suggest that IFN-γ, alongside TNF-α, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.

scholarly journals Olfactory Ecto-Mesenchymal Stem Cell-Derived Exosomes Ameliorate Experimental Colitis via Modulating Th1/Th17 and Treg Cell Responses

2020 ◽  
Vol 11 ◽  
Author(s):  
Jie Tian ◽  
Qiugang Zhu ◽  
Yidan Zhang ◽  
Qianying Bian ◽  
Yue Hong ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cell ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Treg Cells ◽  
Cell Responses ◽  
Resident Stem Cells ◽  
Ifn Γ ◽  
And Function

Olfactory ecto-mesenchymal stem cells (OE-MSCs) are a novel population of resident stem cells in the olfactory lamina propria with strong immunosuppressive function. Exosomes released by MSCs are considered to carry various mRNAs, microRNAs and proteins from cells and function as an extension of MSCs. However, it remains unclear whether exosomes derived from OE-MSCs (OE-MSCs-Exos) possess any immunoregulatory functions. In this study, we found that OE-MSCs-Exos possessed strong suppressive function in CD4+T cell proliferation, accompanied by reduced IL-17, IFN-γ and enhanced TGF-β, IL-10 secreted by T cells. In experimental colitis mice, treatment of OE-MSCs-Exos markedly alleviated the severity of disease, and Th1/Th17 subpopulations were remarkably reduced whereas Treg cells were increased after OE-MSCs-Exos treatment. Mechanistically, OE-MSCs-Exos were demonstrated to inhibit the differentiation of Th1 and Th17 cells, but promote the induction of Treg cells in vitro. Taken together, our findings identified a novel function of OE-MSCs-Exos in regulating T-cell responses, indicating that OE-MSCs-Exos may represent a new cell-free therapy for the treatment of IBD and other inflammatory diseases.

Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3554-3561 ◽  
Author(s):  
Paul Proost ◽  
Evemie Schutyser ◽  
Patricia Menten ◽  
Sofie Struyf ◽  
Anja Wuyts ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Active Form ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Amino Terminal ◽  
Dpp Iv ◽  
Immunodeficiency Virus ◽  
Membrane Bound ◽  
Ifn Γ ◽  
Inducible Protein

Abstract The interferon (IFN)–inducible chemokines, specifically, IFN-γ–inducible protein-10 (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T-cell α-chemoattractant (I-TAC), share a unique CXC chemokine receptor (CXCR3). Recently, the highly specific membrane-bound protease and lymphocyte surface marker CD26/dipeptidyl peptidase IV (DPP IV) was found to be responsible for posttranslational processing of chemokines. Removal of NH2-terminal dipeptides by CD26/DPP IV alters chemokine receptor binding and signaling, and hence inflammatory and anti–human immunodeficiency virus (HIV) activities. CD26/DPP IV and CXCR3 are both markers for Th1 lymphocytes and, moreover, CD26/DPP IV is present in a soluble, active form in human plasma. This study reports that at physiologic enzyme concentrations CD26/DPP IV cleaved 50% of I-TAC within 2 minutes, whereas for IP-10 and Mig the kinetics were 3- and 10-fold slower, respectively. Processing of IP-10 and I-TAC by CD26/DPP IV resulted in reduced CXCR3-binding properties, loss of calcium-signaling capacity through CXCR3, and more than 10-fold reduced chemotactic potency. Moreover, IP-10 and I-TAC cleaved by CD26/DPP IV acted as chemotaxis antagonists and CD26/DPP IV–truncated IP-10 and Mig retained their ability to inhibit the angiogenic activity of interleukin-8 in the rabbit cornea micropocket model. These data demonstrate a negative feedback regulation by CD26/DPP IV in CXCR3-mediated chemotaxis without affecting the angiostatic potential of the CXCR3 ligands IP-10 and Mig.

scholarly journals Natural Killer Cells in the Orchestration of Chronic Inflammatory Diseases

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Luca Parisi ◽  
Barbara Bassani ◽  
Marco Tremolati ◽  
Elisabetta Gini ◽  
Giampietro Farronato ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Chronic Diseases ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Lymphoid Cells ◽  
System Response ◽  
Cell Phenotype ◽  
Killer Cells ◽  
And Function

Inflammation, altered immune cell phenotype, and functions are key features shared by diverse chronic diseases, including cardiovascular, neurodegenerative diseases, diabetes, metabolic syndrome, and cancer. Natural killer cells are innate lymphoid cells primarily involved in the immune system response tonon-self-components but their plasticity is largely influenced by the pathological microenvironment. Altered NK phenotype and function have been reported in several pathological conditions, basically related to impaired or enhanced toxicity. Here we reviewed and discussed the role of NKs in selected, different, and “distant” chronic diseases, cancer, diabetes, periodontitis, and atherosclerosis, placing NK cells as crucial orchestrator of these pathologic conditions.

scholarly journals Toll-Like Receptor Signaling in the Establishment and Function of the Immune System

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1374
Author(s):  
Jahnavi Aluri ◽  
Megan A. Cooper ◽  
Laura G. Schuettpelz
Keyword(s):  
Immune System ◽  
Immune Cell ◽  
System Development ◽  
Cell Types ◽  
Tlr Signaling ◽  
Inborn Errors ◽  
Immune System Dysfunction ◽  
Immune System Development ◽  
And Function ◽  
Immune Defects

Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.

scholarly journals The role of lymphatics in intestinal inflammation

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Ryota Hokari ◽  
Akira Tomioka
Keyword(s):  
Immune Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Dietary Lipid ◽  
Peripheral Tolerance ◽  
Lipid Absorption ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
Lymphocyte Migration ◽  
And Function

AbstractThe lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.

scholarly journals Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

2022 ◽  
Vol 8 ◽  
Author(s):  
Sara La Manna ◽  
Ilaria De Benedictis ◽  
Daniela Marasco
Keyword(s):  
Protein Interactions ◽  
Immune Escape ◽  
Cytokine Signaling ◽  
Protein Protein Interactions ◽  
Extracellular Signals ◽  
Regulate Cell Growth ◽  
Socs Proteins ◽  
Cell Growth And Differentiation ◽  
And Function ◽  
Stat Pathway

The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein–protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK–STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

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