The Role of Interleukin-17A in Inflammatory Bowel Disease-related Neural Plasticity
Moynes, Derek Matthew
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Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal (GI) tract that cause impairments in GI functions, as well as structural and functional plasticity to the innervation of gut that regulates these functions. T helper-17 lymphocytes and interleukin (IL)-17A are crucial to the pathogenesis of IBD and intestinal inflammation. Recent studies in mice report that IL-17A promotes postganglionic sympathetic neurite outgrowth, inhibits voltage-dependent Ca2+ influx and likely contributes to neuroanatomical plasticity within the inflamed GI tract. We hypothesized that IL-17A contributes to sympathetic neuroanatomical remodelling in the colon of patients with IBD and is also capable of signalling to neurons of the enteric nervous system. Mucosal biopsy supernatants from patients with Crohn’s disease (CD) enhanced neurite outgrowth of mouse sympathetic neurons compared to supernatants from control patients. The enhanced outgrowth was abolished when a neutralizing IL-17A antiserum was added. Supernatants from patients with ulcerative colitis did not enhance sympathetic neurite outgrowth, but addition of the neutralizing IL-17A antiserum reduced outgrowth. Despite the growth-promoting effect of the inflammatory milieu from patients with CD, tyrosine hydroxylase-immunoreactivity, a marker of sympathetic axons, was reduced within inflamed regions of resected colon specimens from patients with CD compared to uninflamed regions and control patients without IBD. Since enteric neurons also express the IL-17 receptor-A, we examined the effect of IL-17A on myenteric neuron Ca2+ signaling and neurite outgrowth. Depolarization-induced Ca2+ signaling was doubled in IL-17A-treated neurons relative to controls. IL-17A also increased myenteric neuron neurite complexity, and promoted the proliferation of enteric glial cells. The enhanced neurite complexity was abrogated by the mitotic inhibitor cytosine arabinoside. Although the colons of mice with acute dextran sulphate sodium (DSS) colitis had an elevated amount of IL-17A, there was no difference in myenteric neuron depolarization-induced Ca2+ signaling. Myenteric neurons from mice with acute DSS colitis also had enhanced neurite outgrowth, but a reduction in glial cell proliferation compared to cultures from control mice. These findings suggest that IL-17A signals to the innervation of the gut and likely contributes to the effects of inflammation on these neural circuits.