Ibiza Sales, García-Cassani Bethania, Ribeiro Hélder, Carvalho Tânia, Almeida Luís, Marques Rute, Misic Ana M, Bartow-McKenney Casey, Larson Denise M, Pavan William J, Eberl Gérard, Grice Elizabeth A, Veiga-Fernandes Henrique
Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
Microenvironment and Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
Nature. 2016 Jul 21;535(7612):440-443. doi: 10.1038/nature18644. Epub 2016 Jul 13.
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.
第3组固有淋巴细胞（ILC3）是黏膜屏障处炎症和感染的主要调节因子。ILC3的发育被认为是预先设定好的，但ILC3如何感知、整合并响应局部环境信号仍不清楚。在此，我们表明小鼠中的ILC3能够感知其环境，并作为由神经营养因子精心协调的神经胶质细胞-ILC3-上皮细胞单元的一部分来控制肠道防御。我们发现肠道ILC3表达神经调节受体RET。ILC3自主缺失Ret会导致固有白细胞介素-22（IL-22）减少、上皮反应性受损、菌群失调以及对肠道炎症和感染的易感性增加。神经营养因子直接在p38丝裂原活化蛋白激酶/细胞外信号调节激酶-蛋白激酶B（MAPK/ERK-AKT）级联反应和信号转导子和转录激活子3（STAT3）激活的下游控制固有Il22。值得注意的是，ILC3与表达神经营养因子的神经胶质细胞相邻，这些神经胶质细胞向ILC3聚集体伸出星状突起。神经胶质细胞以一种髓样分化初级反应蛋白88（MYD88）依赖的方式感知微环境线索，以控制神经营养因子和固有IL-22。因此，神经胶质细胞固有Myd88缺失会导致ILC3衍生的IL-22产生受损以及对肠道炎症和感染的明显易感性。我们的工作揭示了一个新型的多组织防御单元，表明神经胶质细胞是神经营养因子信号对神经元和固有免疫调节的核心枢纽。
