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Immunity. 2019 Feb 19;50(2):446-461.e9. doi: 10.1016/j.immuni.2018.12.020. Epub 2019 Jan 29.

Microbiota Sensing by Mincle-Syk Axis in Dendritic Cells Regulates Interleukin-17 and -22 Production and Promotes Intestinal Barrier Integrity.

Author information

1
Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain.
2
Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain; Department of Immunology, School of Medicine, Universidad Complutense de Madrid, 12 de Octubre Health Research Institute (imas12), Madrid, Spain. Electronic address: siborra@ucm.es.
3
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
4
Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK; Manchester Collaborative Centre for Inflammation Research, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
5
Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.
6
INRA Micalis Institut, UMR1319, AgroParisTech, Université Paris-Saclay, 78350 Jouy-en-Josas, France; INSERM UMR1163, Institut Imagine, Laboratory of Intestinal Immunity, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75006 Paris, France.
7
Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León 62, Madrid 28006, Spain.
8
Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, Urbanización Montepríncipe, km 0, M501, Alcorcón 28925, Spain.
9
MiltenyiBiotec GmbH, Bergisch Gladbach, Germany.
10
Institute of Food, Nutrition, and Health, ETH Zurich, Vladimir-Prelog-Weg 4, Zürich 8093, Switzerland.
11
Medimmune, Granta Park, Cambridge CB21 6GH, UK.
12
INSERM UMR1163, Institut Imagine, Laboratory of Intestinal Immunity, 75015 Paris, France; Université Paris Descartes-Sorbonne Paris Cité, 75006 Paris, France.
13
Section of Immunology, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 266a Zurich 8057, Switzerland.
14
Immunobiology Laboratory, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, Madrid 28029, Spain. Electronic address: dsancho@cnic.es.

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:

IL-17; IL-22; Mincle; Syk kinase; T lymphocyte; antimicrobial defense; dendritic cell; gut microbiota translocation; innate lymphoid cells; intestinal barrier; lipid metabolism; liver inflammation

PMID:
30709742
PMCID:
PMC6382412
DOI:
10.1016/j.immuni.2018.12.020
[Indexed for MEDLINE]
Free PMC Article

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