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

• Published in: Immunity (Cambridge, Mass.) Vol. 50; no. 2; pp. 446 - 461.e9
• Main Authors: Martínez-López, María, Iborra, Salvador, Conde-Garrosa, Ruth, Mastrangelo, Annalaura, Danne, Camille, Mann, Elizabeth R., Reid, Delyth M., Gaboriau-Routhiau, Valérie, Chaparro, Maria, Lorenzo, María P., Minnerup, Lara, Saz-Leal, Paula, Slack, Emma, Kemp, Benjamin, Gisbert, Javier P., Dzionek, Andrzej, Robinson, Matthew J., Rupérez, Francisco J., Cerf-Bensussan, Nadine, Brown, Gordon D., Bernardo, David, LeibundGut-Landmann, Salomé, Sancho, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-02-2019; Elsevier Limited; Cell Press
• Subjects: Animals; Antigens; antimicrobial defense; CD11c antigen; CD4 antigen; Commensals; dendritic cell; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Depletion; Deregulation; Digestive system; Gastrointestinal Microbiome - immunology; Gastrointestinal Microbiome - physiology; Gastrointestinal tract; gut microbiota translocation; Helper cells; Humans; IL-17; IL-22; Immune system; Immunoglobulin A; Inflammation; innate lymphoid cells; Interleukin 17; Interleukin 22; Interleukin 6; Interleukin-17 - immunology; Interleukin-17 - metabolism; Interleukins - immunology; Interleukins - metabolism; intestinal barrier; Intestinal microflora; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestine; Investigations; Kinases; Laboratories; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Lectins, C-Type - metabolism; Ligands; Lipid metabolism; Lipids; Liver; liver inflammation; Lymphocytes; Lymphocytes T; Lymphoid cells; Membrane Proteins - genetics; Membrane Proteins - immunology; Membrane Proteins - metabolism; Metabolism; Mice, Inbred C57BL; Mice, Knockout; Microbiota; Mincle; Mucosa; Mutualism; Peptides; Peyer's Patches - immunology; Peyer's Patches - metabolism; Peyer's Patches - microbiology; Signal transduction; Signal Transduction - immunology; Signaling; Statistical analysis; Syk kinase; Syk Kinase - genetics; Syk Kinase - immunology; Syk Kinase - metabolism; Syk protein; T lymphocyte; Th17 Cells - immunology; Th17 Cells - metabolism; Translocation; Syk kinase; intestinal barrier; IL-17; lipid metabolism; Mincle; liver inflammation; T lymphocyte; innate lymphoid cells; IL-22; gut microbiota translocation; dendritic cell; antimicrobial defense
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.12.020

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.
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•Mincle detects mucosal commensals and triggers IL-6 and IL-23p19 in PPs•LysoDC and CD11b+ DC from PPs prime a microbiota- and Mincle-Syk-dependent IL-17•Gut Th17 and ILCs producing IL-17 and IL-22 require Mincle and Syk in CD11c+ cells•Mincle promotes the gut barrier, limiting microbial translocation and liver inflammation
Martínez-López et al. explore host signaling pathways linking recognition of commensal microbes and Th17 differentiation. They find that the Mincle-Syk axis in Peyer’s patch DCs detects mucosal-resident bacteria, inducing IL-6 and IL-23p19 and stimulating IL-17 and IL-22 production by intestinal T cells and ILCs, which control the intestinal immune barrier function.