Th17 Cells Induce Colitis and Promote Th1 Cell Responses through IL-17 Induction of Innate IL-12 and IL-23 Production

Feng, Ting; Qin, Hongwei; Wang, Lanfang; Benveniste, Etty N.; Elson, Charles O.; Cong, Yingzi

doi:10.4049/jimmunol.1001454

Cited by 164 publications

(157 citation statements)

References 78 publications

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“…Massive infiltration of Th17 cells was also detected in IBD patients [76]. Based on the accumulating evidence, Th17 cells also contribute to the pathogenesis of IBD and show more potent capacity than Th1 cells in the induction of colitis [77]. This finding might be explained by the conversion of Th17 cells to Th1 cells via induction of mucosal IL-23 production in IBD patients [77].…”

Section: Th17 and Ibdmentioning

confidence: 89%

Th17 cells in autoimmune diseases

et al. 2015

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Th17 cells are a new subset of CD4(+) T cells involved in the clearance of extracellular pathogens and fungi. Accumulating evidence suggests that Th17 cells and their signature cytokines have a pivotal role in the pathogenesis of multiple autoimmune-mediated inflammatory diseases. Here, we summarize recent research progress on Th17 function in the development and pathogenesis of autoimmune diseases. We also propose to identify new small molecule compounds to manipulate Th17 function for potential therapeutic application to treat human autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, inflammatory bowel disease, and multiple sclerosis.

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Section: Th17 and Ibdmentioning

confidence: 89%

Th17 cells in autoimmune diseases

et al. 2015

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“…Th17 cells are maintained by IL-23 and produce IL-17 (40). Transfer of Th17 cells into mice with a fully functional innate immune system potently induces colitis (41). Thus, Th1/Th17 cell responses play a major role in the onset of colitis.…”

Section: Discussionmentioning

confidence: 99%

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

Lee

Moraes‐Vieira

Castoldi

et al. 2016

Journal of Biological Chemistry

114

124

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We recently discovered a structurally novel class of endogenous lipids, branched palmitic acid esters of hydroxy stearic acids (PAHSAs), with beneficial metabolic and anti-inflammatory effects. We tested whether PAHSAs protect against colitis, which is a chronic inflammatory disease driven predominantly by defects in the innate mucosal barrier and adaptive immune system. There is an unmet clinical need for safe and well tolerated oral therapeutics with direct anti-inflammatory effects. Wild-type mice were pretreated orally with vehicle or 5-PAHSA (10 mg/kg) and 9-PAHSA (5 mg/kg) once daily for 3 days, followed by 10 days of either 0% or 2% dextran sulfate sodium water with continued vehicle or PAHSA treatment. The colon was collected for histopathology, gene expression, and flow cytometry. Intestinal crypt fractions were prepared for ex vivo bactericidal assays. Bone marrow-derived dendritic cells pretreated with vehicle or PAHSA and splenic CD4 ؉ T cells from syngeneic mice were co-cultured to assess antigen presentation and T cell activation in response to LPS. PAHSA treatment prevented weight loss, improved colitis scores (stool consistency, hematochezia, and mouse appearance), and augmented intestinal crypt Paneth cell bactericidal potency via a mechanism that may involve GPR120. In vitro, PAHSAs attenuated dendritic cell activation and subsequent T cell proliferation and Th1 polarization. The anti-inflammatory effects of PAHSAs in vivo resulted in reduced colonic T cell activation and pro-inflammatory cytokine and chemokine expression. These anti-inflammatory effects appear to be partially GPR120-dependent. We conclude that PAHSA treatment regulates innate and adaptive immune responses to prevent mucosal damage and protect against colitis. Thus, PAHSAs may be a novel treatment for colitis and related inflammation-driven diseases.Lipids have been a rich source of chemical matter for the development of new medicines (1). Endogenous small-molecule metabolites are another class of natural products made within the human body that have important biological activities (2). For example, the discovery and synthesis of prostaglandins revealed their diverse biological roles as autocrine and paracrine mediators in many tissues. This led to their development as therapeutic agents for a variety of indications ranging from vasodilatation to glaucoma treatment (3-6). More recently, compounds that target the sphingosine 1 receptors are emerging as novel therapeutics for autoimmune diseases (7). Thus, the discovery and characterization of bioactive lipids is of fundamental interest with broad impact. We recently discovered a structurally novel class of lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), 6 with anti-diabetic and anti-inflammatory properties (8). These lipids are products of endogenous synthesis in mammalian tissues and are also present in food. There are more than 16 FAHFA families, and each family is distinguished by having a different fatty acid and hydroxy fatty acid composition. Furthermor...

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“…We show that CD4 conditioning resident APCs. Moreover, this early IL-17 production may also act directly on APCs, such as macrophages and subsets of DCs, which are known to express IL-17R more abundantly than T cells, and provoke APC production of IL-23, IL-1, IL-6 and TGF-b1 [37,55], which are crucial factors for pathogenic Th17-cell development. Consistently, IL-17 secretion is significantly more elevated in mucosal tissues, where we detected an elevated level of IL-1b and IL-6 mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

2011

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Foxp31 regulatory T (T REG ) cells are critical mediators of peripheral immune tolerance, and abrogation of their function provokes a variety of autoimmune and inflammatory states including inflammatory bowel disease. In this study, we investigate the functional dynamics of T REG -cell responses in a CD4) hosts to gain insights into the mechanism and cellular targets of suppression in vivo. We show that CD4 1 T effector cell transfer into T-cell-deficient mice rapidly induces mucosal inflammation and colitis development, which is associated with prominent Th1 and Th17 responses. Interestingly, we unveil a prominent role for resident cd T cells in mucosal inflammation as they promote Th1 and particularly Th17 responses in the early phase of inflammation, thus exacerbating colitis development. We further demonstrate that CD4

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Th17 Cells Induce Colitis and Promote Th1 Cell Responses through IL-17 Induction of Innate IL-12 and IL-23 Production

Cited by 164 publications

References 78 publications

Th17 cells in autoimmune diseases

Th17 cells in autoimmune diseases

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

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Th17 Cells Induce Colitis and Promote Th1 Cell Responses through IL-17 Induction of Innate IL-12 and IL-23 Production

Cited by 164 publications

References 78 publications

Th17 cells in autoimmune diseases

Th17 cells in autoimmune diseases

Branched Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) Protect against Colitis by Regulating Gut Innate and Adaptive Immune Responses

CD4+Foxp3+ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

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CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation