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Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence

机译：胶质细胞源性神经调节剂控制3型先天淋巴样细胞和肠道防御

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摘要

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.
机译：第3组先天淋巴样细胞（ILC3）是黏膜屏障炎症和感染的主要调节剂（1）。 ILC3的开发被认为是经过编程的（1），但是ILC3如何感知，整合和响应本地环境信号仍不清楚。在这里，我们显示ILC3在小鼠中感觉到其环境并控制肠道防御，这是神经营养因子精心安排的神经胶质ILC3上皮细胞单位的一部分。我们发现肠ILC3表达神经调节受体RET。 ILC3自主性Ret消融导致先天性白介素22（IL-22）减少，上皮反应性受损，营养不良以及对肠道炎症和感染的敏感性增加。神经营养因子直接控制p38 MAPK / ERK-AKT级联反应和STAT3激活下游的固有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，这些神经胶质细胞在ILC3聚集体中呈星状突起。胶质细胞以MYD88依赖性方式感知微环境提示，以控制神经营养因子和先天性IL-22。因此，神经胶质本征Myd88缺失导致ILC3衍生的IL-22的生产受损，并明显倾向于肠道炎症和感染。我们的工作揭示了新型的多组织防御单元，揭示了神经胶质细胞是神经元和神经营养因子信号固有免疫调节的中心枢纽。

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  • 来源
    《Nature》 |2016年第7612期|440-443|共4页
  • 作者

    Ibiza Sales; Garcia-Cassani Bethania; Ribeiro Helder; Carvalho Tania; Almeida Luis; Marques Rute; Misic Ana M.; Bartow-McKenney Casey; Larson Denise M.; Pavan William J.; Eberl Gerard; Grice Elizabeth A.; Veiga-Fernandes Henrique;

  • 作者单位

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal;

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal;

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal;

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal;

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal;

    Inst Pasteur, Microenvironm & Immun Unit, 25 Rue Docteur Roux, F-75724 Paris, France|INSERM, U1163, Lab Intestinal Immun, Paris, France|Univ Paris 05, Sorbonne Paris Cite, Paris, France|Inst Imagine, Paris, France;

    Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1007 Biomed Res Bldg, Philadelphia, PA 19104 USA|Univ Penn, Sch Vet Med, Dept Pathobiol, Ctr Host Microbial Interact, Philadelphia, PA 19104 USA;

    Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1007 Biomed Res Bldg, Philadelphia, PA 19104 USA;

    NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA;

    NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA;

    Inst Pasteur, Microenvironm & Immun Unit, 25 Rue Docteur Roux, F-75724 Paris, France;

    Univ Penn, Dept Dermatol, Perelman Sch Med, 421 Curie Blvd,1007 Biomed Res Bldg, Philadelphia, PA 19104 USA;

    Fac Med Lisbon, Inst Med Mol, Ave Prof Egas Moniz,Edificio Egas Moniz, P-1649028 Lisbon, Portugal|Champalimaud Ctr Unknown, Champalimaud Res, P-1400038 Lisbon, Portugal;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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