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      IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T cell-mediated colitis

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          Abstract

          Polymorphisms attenuating IL-10 signaling confer genetic risk for inflammatory bowel disease. Yet how IL-10 prevents mucosal autoinflammation is incompletely understood. We demonstrate using lineage-specific deletions of IL-10Rα that IL-10 acts primarily through macrophages to limit colitis. Colitis depends on IL-6 to support pathologic Th17 cell generation in wild type mice. However, specific ablation of macrophage IL-10Rα provokes excessive IL-1β production that overrides Th17 IL-6 dependence, amplifying the colonic Th17 response and disease severity. IL-10 not only inhibits pro-IL-1β production transcriptionally in macrophages, but suppresses caspase-1 activation and caspase-1 dependent maturation of pro-IL-1β to IL-1β. Therefore lineage-specific effects of IL-10 skew the cytokine dependency of Th17 development required for colitis pathogenesis. Coordinated interventions may be needed to fully suppress Th17-mediated immunopathology.

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          Most cited references 54

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          Interleukin-10 and the interleukin-10 receptor.

          Interleukin-10 (IL-10), first recognized for its ability to inhibit activation and effector function of T cells, monocytes, and macrophages, is a multifunctional cytokine with diverse effects on most hemopoietic cell types. The principal routine function of IL-10 appears to be to limit and ultimately terminate inflammatory responses. In addition to these activities, IL-10 regulates growth and/or differentiation of B cells, NK cells, cytotoxic and helper T cells, mast cells, granulocytes, dendritic cells, keratinocytes, and endothelial cells. IL-10 plays a key role in differentiation and function of a newly appreciated type of T cell, the T regulatory cell, which may figure prominently in control of immune responses and tolerance in vivo. Uniquely among hemopoietic cytokines, IL-10 has closely related homologs in several virus genomes, which testify to its crucial role in regulating immune and inflammatory responses. This review highlights findings that have advanced our understanding of IL-10 and its receptor, as well as its in vivo function in health and disease.
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            The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells.

            IL-17-producing T lymphocytes have been recently shown to comprise a distinct lineage of proinflammatory T helper cells, termed Th17 cells, that are major contributors to autoimmune disease. We show here that the orphan nuclear receptor RORgammat is the key transcription factor that orchestrates the differentiation of this effector cell lineage. RORgammat induces transcription of the genes encoding IL-17 and the related cytokine IL-17F in naïve CD4(+) T helper cells and is required for their expression in response to IL-6 and TGF-beta, the cytokines known to induce IL-17. Th17 cells are constitutively present throughout the intestinal lamina propria, express RORgammat, and are absent in mice deficient for RORgammat or IL-6. Mice with RORgammat-deficient T cells have attenuated autoimmune disease and lack tissue-infiltrating Th17 cells. Together, these studies suggest that RORgammat is a key regulator of immune homeostasis and highlight its potential as a therapeutic target in inflammatory diseases.
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              Protective and pathogenic functions of macrophage subsets.

              Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis. We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing. Finally, we briefly discuss the characterization of macrophage heterogeneity in humans.
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                Author and article information

                Journal
                101528555
                37539
                Nat Commun
                Nat Commun
                Nature communications
                2041-1723
                19 December 2014
                21 January 2015
                21 July 2015
                : 6
                : 6131
                Affiliations
                [1 ]Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl., Memphis, TN 38105
                [2 ]Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl., Memphis, TN 38105
                Author notes
                [3 ]Correspondence: Terrence L. Geiger, M.D., Ph.D., Member, Department of Pathology, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl., MS 342, Memphis, TN 38105, terrence.geiger@ 123456stjude.org , Tel: (901) 595-3359
                Article
                NIHMS650283
                10.1038/ncomms7131
                4302761
                25607885
                Categories
                Article

                Uncategorized

                il-10, il-1β, macrophage, th17, inflammasome

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