Glial-cell-derived Neuroregulators Control Type 3 Innate Lymphoid Cells and Gut Defence

Overview

Journal Nature

Specialty Science

Date 2016 Jul 14

PMID 27409807

Citations 185

Authors

Sales Ibiza

Bethania Garcia-Cassani

Helder Ribeiro

Tania Carvalho

Luis Almeida

Rute Marques

Ana M Misic

Casey Bartow-McKenney

Denise M Larson

William J Pavan

Gerard Eberl

Elizabeth A Grice

Henrique Veiga-Fernandes

Affiliations

Soon will be listed here.

Abstract

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers. ILC3 development is thought to be programmed, but how ILC3 perceive, integrate and respond to local environmental signals remains unclear. Here we show that ILC3 in mice sense their environment and control gut defence as part of a glial–ILC3–epithelial cell unit orchestrated by neurotrophic factors. We found that enteric ILC3 express the neuroregulatory receptor RET. ILC3-autonomous Ret ablation led to decreased innate interleukin-22 (IL-22), impaired epithelial reactivity, dysbiosis and increased susceptibility to bowel inflammation and infection. Neurotrophic factors directly controlled innate Il22 downstream of the p38 MAPK/ERK-AKT cascade and STAT3 activation. Notably, ILC3 were adjacent to neurotrophic-factor-expressing glial cells that exhibited stellate-shaped projections into ILC3 aggregates. Glial cells sensed microenvironmental cues in a MYD88-dependent manner to control neurotrophic factors and innate IL-22. Accordingly, glial-intrinsic Myd88 deletion led to impaired production of ILC3-derived IL-22 and a pronounced propensity towards gut inflammation and infection. Our work sheds light on a novel multi-tissue defence unit, revealing that glial cells are central hubs of neuron and innate immune regulation by neurotrophic factor signals.

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