4 years ago

Continuous IL-23 stimulation drives ILC3 depletion in the upper GI tract and, in combination with TNFα, induces robust activation and a phenotypic switch of ILC3

Jesus Paez-Cortez, Wendy Waegell, Shaughn Bryant, Amanda M. Schmidt Paustian, Gillian Kingsbury, Susan Westmoreland

by Amanda M. Schmidt Paustian, Jesus Paez-Cortez, Shaughn Bryant, Susan Westmoreland, Wendy Waegell, Gillian Kingsbury

Mutations in the Interleukin (IL)-23/IL-23 receptor loci are associated with increased inflammatory bowel disease (IBD) susceptibility, and IL-23 neutralization has shown efficacy in early clinical trials. To better understand how an excess of IL-23 affects the gastrointestinal tract, we investigated chronic systemic IL-23 exposure in healthy wildtype mice. As expected, IL-23 exposure resulted in early activation of intestinal type 3 innate lymphoid cells (ILC3), followed by infiltration of activated RORγt+ T helper cells. Surprisingly, however, sustained IL-23 stimulus also dramatically reduced classical ILC3 populations within the proximal small intestine, and a phenotypically distinct T-bet expressing ILC3 population emerged. TNFα neutralization, a widely used IBD therapy, reduced several aspects of the IL-23 driven ILC3 response, suggesting a synergy between IL-23 and TNFα in ILC3 activation. In vitro studies supported these findings, revealing previously unappreciated effects of IL-23 and TNFα within the intestine.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.pone.0182841

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