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.

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

doi:10.1371/journal.pone.0182841

Amanda M Schmidt Paustian, Gillian Kingsbury + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0182841

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Journal: PloS one	Publication Date: Aug 8, 2017
Citations: 13	License type: CC BY 4.0

Affiliation: AbbVie (United States)

Abstract

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.

Highlights

Interleukin (IL)-23 has been associated with the development of several debilitating autoimmune diseases, including psoriasis and inflammatory bowel disease (IBD) [1]
Studies performed in IL-23 receptor (IL-23R) reporter mice have shown that T cells and innate lymphoid cell (ILC) populations residing within the lamina propria (LP) are the primary responders to IL-23 in the healthy GI tract [3]
Flow cytometric analysis of isolated LP cells revealed hematopoietic cell infiltration by 3 days post IL-23 mc injection, which became more dramatic by 2 weeks (Fig 1B)

Summary

Introduction

Interleukin (IL)-23 has been associated with the development of several debilitating autoimmune diseases, including psoriasis and inflammatory bowel disease (IBD) [1]. Examination of intestinal pathology in IL-23 mc injected mice revealed inflammation and lengthening of the small intestine (SI); and a dramatic activation and loss of RORγt+ ILC3 populations from the LP was observed.

Results

Conclusion