@article{d63e672db21240b8bf4ce294d3886581,
title = "Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity",
abstract = "Production of interleukin-17 (IL-17) and IL-22 by T helper 17 (Th17) cells and group 3 innate lymphoid cells (ILC3s) in response to the gut microbiota ensures maintenance of intestinal barrier function. Here, we examined the mechanisms whereby the immune system detects microbiota in the steady state. A Syk-kinase-coupled signaling pathway in dendritic cells (DCs) was critical for commensal-dependent production of IL-17 and IL-22 by CD4+ T cells. The Syk-coupled C-type lectin receptor Mincle detected mucosal-resident commensals in the Peyer's patches (PPs), triggered IL-6 and IL-23p19 expression, and thereby regulated function of intestinal Th17- and IL-17-secreting ILCs. Mice deficient in Mincle or with selective depletion of Syk in CD11c+ cells had impaired production of intestinal RegIIIγ and IgA and increased systemic translocation of gut microbiota. Consequently, Mincle deficiency led to liver inflammation and deregulated lipid metabolism. Thus, sensing of commensals by Mincle and Syk signaling in CD11c+ cells reinforces intestinal immune barrier and promotes host-microbiota mutualism, preventing systemic inflammation.",
keywords = "intestinal barrier, dendritic cell, T lymphocyte, innate lymphoid cells, Minkle, Syk kinase, IL-17, IL-22, antimicrobial defense, gut microbiota translocation, liver inflammation, lipid metabolism, Mincle, IGA, C-TYPE LECTIN, COMMENSAL BACTERIA, ROR-GAMMA-T, PEYERS-PATCHES, INDUCTION, INNATE LYMPHOID-CELLS, ADAPTIVE IMMUNITY, T(H)17 CELLS, DIFFERENTIATION",
author = "Mar{\'i}a Mart{\'i}nez-L{\'o}pez and Salvador Iborra and Ruth Conde-Garrosa and Annalaura Mastrangelo and Camille Danne and Mann, {Elizabeth R} and Reid, {Delyth M} and Val{\'e}rie Gaboriau-Routhiau and Maria Chaparro and Lorenzo, {Mar{\'i}a P} and Lara Minnerup and Paula Saz-Leal and Emma Slack and Benjamin Kemp and Gisbert, {Javier P} and Andrzej Dzionek and Robinson, {Matthew J} and Rup{\'e}rez, {Francisco J} and Nadine Cerf-Bensussan and Brown, {Gordon D} and David Bernardo and Salom{\'e} LeibundGut-Landmann and David Sancho",
note = "We are grateful to members of the D.S. laboratory and Dr. E. Fern{\'a}ndez-Malav{\'e} for discussions and critical reading of the manuscript. We appreciate the support of A. Tom{\'a}s-Loba, G. Sabio, P. Mart{\'i}n, A. Tsilingiri, A.R. Ramiro, C.L. Abram, C.A. Lowell, J.M. Garc{\'i}a-Lobo, M. Molina, and M.C. Rodr{\'i}guez for providing reagents and support. We thank the staff at the Fundaci{\'o}n Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) facilities for technical support. M.M.-L. received a Formaci{\'o}n de Personal Universitario (FPU) fellowship (AP2010-5935) from the Spanish Ministerio de Educaci{\'o}n. S.I. is funded by grant SAF2015-74561-JIN from the Spanish Ministerio de Ciencia, Innovaci{\'o}n, y Universidades (MCIU) and Fondos Europeos de Desarrollo Regional (FEDER). G.D.B and D.M.R. are supported by the Wellcome Trust and the MRC Centre for Medical Mycology at the University of Aberdeen. S.L.L. is supported by the Swiss National Science Foundation (PP00P3_150758). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, the Agencia Estatal de Investigaci{\'o}n, and FEDER; B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MCIU, and FEDER; the Acteria Foundation; the Constantes y Vitales prize (Atresmedia); La Marat{\'o} de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020), and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).",
year = "2019",
month = feb,
day = "19",
doi = "10.1016/j.immuni.2018.12.020",
language = "English",
volume = "50",
pages = "446--461",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "2",
}
