title: Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence.
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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Sales
authors.initials: S
authors.lastname: Ibiza
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Bethania
authors.initials: B
authors.lastname: García-Cassani
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Hélder
authors.initials: H
authors.lastname: Ribeiro
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Carvalho
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Almeida
authors.affiliation: Microenvironment and Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
authors.forename: Rute
authors.initials: R
authors.lastname: Marques
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Misic
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US.
authors.forename: Casey
authors.initials: C
authors.lastname: Bartow-McKenney
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Larson
authors.affiliation: Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.affiliation: Microenvironment and Immunity Unit, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.affiliation: Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Blvd, 1007 Biomedical Research Building, Philadelphia, PA 19104, US.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grice
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.|Champalimaud Research. Champalimaud Centre for the Unknown. 1400-038 Lisbon, Portugal.
authors.forename: Henrique
authors.initials: H
authors.lastname: Veiga-Fernandes
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D000069196:Gastrointestinal Microbiome / Q000276:immunology; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000172:deficiency / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D053594:Myeloid Differentiation Factor 88; D018377:Neurotransmitter Agents; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C507780:Myd88 protein, mouse; C494087:Stat3 protein, mouse; C494999:Ret protein, mouse; C514862:Akt1 protein, mouse