Abstract
IL-36 cytokines are emerging as potent orchestrators of intestinal inflammation and are being implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the mechanisms through which these cytokines mediate these effects remain to be fully uncovered. Here, we report specifically elevated expression of IL-36α, and not IL-36β or IL-36γ in the serum of newly diagnosed, treatment naïve, paediatric IBD patients and identify T cells as primary cellular mediators of IL-36 responses in the inflamed gut. IL-36R expression on CD4+ T cells was found to promote intestinal pathology in a murine model of colitis. Consistent with these effects, IL-36R can act as a potent instructor of CD4+ T cell differentiation in vivo, enhancing Th1 responses, while inhibiting the generation of Tregs. In addition, loss of IL-36 responsiveness significantly reduced the migration of pathogenic CD4+ T cells towards intestinal tissues and IL-36 was found to act, uniquely among IL-1 family members, to induce the expression of gut homing receptors in proinflammatory murine and human CD4+ T cells. These data reveal an important role for IL-36 cytokines in driving the colitogenic potential of CD4+ T cells and identify a new mechanism through which they may contribute to disease pathogenesis.
Highlights
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract
To determine the effect of IL-36 signalling on T cell driven colitis, we FACs sorted both wt and Il36r−/− CD4+CD25−CD45Rbhi T effector cells, transferred them to Rag1−/− recipients, and whether protein expression of the IL-36 family members are compared the pathogenesis of disease between the groups
Mice altered in the periphery at the earliest stages in the pathogenesis receiving Il36r−/− T cells were found to exhibit significantly less of inflammatory bowel diseases (IBD)
Summary
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract It is typically subcategorised into two physiologically distinct disorders, Crohn’s Disease (CD), in which pathology can present anywhere along the GI tract, and Ulcerative Colitis (UC), a condition which mainly presents in the colon.[1] In western society incidence of this disease is on the rise, and ~25% of cases arise in childhood or adolescence.[1,2,3]. In both adults and paediatric patients, the ultimate goal of current treatment strategies is to offer symptomatic relief and induce and maintain remission. New approaches and targets are required to meet what remains a large burden of unmet need
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