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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Gastrointestinal Microbiome / immunology*
  • Gastrointestinal Microbiome / physiology
  • Humans
  • Interleukin-17 / immunology*
  • Interleukin-17 / metabolism
  • Interleukins / immunology*
  • Interleukins / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / microbiology
  • Lectins, C-Type / genetics
  • Lectins, C-Type / immunology*
  • Lectins, C-Type / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peyer's Patches / immunology
  • Peyer's Patches / metabolism
  • Peyer's Patches / microbiology
  • Signal Transduction / immunology
  • Syk Kinase / genetics
  • Syk Kinase / immunology*
  • Syk Kinase / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism

Substances

  • Clecsf8 protein, mouse
  • Interleukin-17
  • Interleukins
  • Lectins, C-Type
  • Membrane Proteins
  • Syk Kinase
  • interleukin-22