A role for interleukin-17a as a mediator of sympathetic neuroanatomical remodelling during experimental colitis.

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Cervi, Andrea Lee
inflammation , neuroanatomical plasticity , sympathetic nervous system
Sympathetic catecholamines and co-transmitters released within the gastrointestinal (GI) tract provide dynamic regulation of gut motility, fluid secretion, blood flow and immune cell function. Pathological GI inflammation in patients with inflammatory bowel diseases (IBD) evokes functional and structural plasticity in sympathetic neurons that innervate the gut, which may contribute to symptom generation. The mechanisms responsible for aberrant sympathetic behaviour during colonic inflammation remain elusive, though evidence points to a role for mediators of the mucosal immune response. Interleukin (IL)-17 is the principal cytokine of the novel TH17 lineage of helper T cells. Based on mounting clinical, genetic and experimental evidence, IL-17 is thought to play a pivotal role in the immunopathogenesis of IBD. However, nothing is known of the contribution of IL-17 to sympathetic neuroplasticity during chronic inflammatory disease. We hypothesized that remodelling of postganglionic sympathetic axons occurs in response to exposure of axons to the inflamed colonic milieu and that IL-17 serves as the primary mediator of this neuroanatomical remodelling. An increase in tyrosine hydroxylase (TH) immunoreactivity, a marker of sympathetic axons, was observed in the muscularis externae and mucosae of colons from mice subjected to acute and chronic models of dextran sulphate sodium (DSS)-induced colitis. In parallel, we found markedly elevated levels of IL-17 in the serum and colonic tissues of mice with colitis. To investigate whether the colitis microenvironment promoted axonal growth, distal neurites of adult sympathetic neurons from the superior mesenteric ganglion (SMG) were incubated in supernatant collected from explant cultures of inflamed colon. Colitis supernatant enhanced neurite outgrowth from gut-projecting SMG neurons compared to supernatants from control colon. Importantly, this effect was abrogated following the addition of IL-17-neutralising antiserum to cultures. Moreover, IL-17 increased the morphological complexity of SMG neurites in vitro while none of the other inflammatory cytokines known to be elevated during IBD had a similar effect. These findings suggest a novel role for IL-17 as a mediator of sympathetic neuroanatomical plasticity during colonic inflammation. Whether this contributes to the functional deficits and chronic inflammatory response that occurs in the GI tract during IBD remains to be determined.
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