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IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE129215 | GEO | 2019/04/03

REPOSITORIES: GEO

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IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response.

Project description:Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre:Il10rafl/fl:Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs.

| S-EPMC6697185 | biostudies-literature

IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 2]

Project description:we define critical cell-type-specific contributions to the induction and effector mechanism of macrophage-driven colitis, as manifested in mice harboring IL-10R deficiencies and human IBD pathologies

2019-04-03 | GSE129212 | GEO

IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 1]

2019-04-03 | GSE129211 | GEO

IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response

Project description:IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response

| PRJNA530535 | ENA

IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 1]

Project description:IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 1]

| PRJNA530540 | ENA

IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 2]

Project description:IL-23 producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven pro-inflammatory epithelial cell response [dataset 2]

| PRJNA530543 | ENA

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12R?1.

Project description:Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12R?1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

| S-EPMC5773378 | biostudies-literature

IL-23 signaling regulation of pro-inflammatory T-cell migration uncovered by phosphoproteomics.

Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here, we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells and found 168 phosphorylations regulated upon IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ17 cells. IL-23-induced RLC phosphorylation required Janus kinase 2 (JAK2) and Rho-associated protein kinase (ROCK) catalytic activity, and further study of the IL-23/ROCK connection revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells through ROCK activation. In addition, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work (i) provides new insights into phosphorylation networks that control Th17 cells, (ii) widely expands the current knowledge on IL-23 signaling, and (iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.

| S-EPMC7117768 | biostudies-literature

mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production.

Project description:It has been shown recently that neutrophils are able to produce IL-22 and IL-17, which differentially regulate the pathogenesis of inflammatory bowel disease. However, it is still largely unknown how the neutrophil production of IL-22 and IL-17 is regulated, and their role in the pathogenesis of inflammatory bowel disease. In this study, we found that IL-23 promoted neutrophil production of IL-17 and IL-22. IL-23 stimulated the neutrophil expression of IL-23R as well as rorc and ahr. Retinoid acid receptor-related orphan receptor ? t and aryl-hydrocarbon receptor differentially regulated IL-23 induction of neutrophil IL-17 and IL-22. In addition, IL-23 induced the activation of mTOR in neutrophils. Blockade of the mTOR pathway inhibited IL-23-induced expression of rorc and ahr, as well as IL-17 and IL-22 production. By using a microbiota Ag-specific T cell-mediated colitis model, we demonstrated that depletion of neutrophils, as well as blockade of IL-22, resulted in a significant increase in the severity of colitis, thereby indicating a protective role of neutrophils and IL-22 in chronic colitis. Collectively, our data revealed that neutrophils negatively regulate microbiota Ag-specific T cell induction of colitis, and IL-23 induces neutrophil production of IL-22 and IL-17 through induction of rorc and ahr, which is mediated by the mTOR pathway.

| S-EPMC4868807 | biostudies-literature

IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.

Project description:BackgroundPsoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear.ObjectiveTo examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD.MethodsSkin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry.ResultsIn peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity.ConclusionOur data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.

| S-EPMC2874584 | biostudies-literature

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