期刊
NATURE
卷 535, 期 7612, 页码 440-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature18644
关键词
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资金
- MEC, Spain
- FCT, Portugal
- EU [289720]
- EMBO [1648]
- ERC, EU [647274]
- Kenneth Rainin Foundation, US
- Crohn's and Colitis Foundation of America, US
- Institut Pasteur
- ANR, France
- NIH NIAMS [R01 AR060873, T32 AR007465]
- Morris Animal Foundation [D14CA-404]
- European Research Council (ERC) [647274] Funding Source: European Research Council (ERC)
Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation and infection at mucosal barriers(1). ILC3 development is thought to be programmed(1), 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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