Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence

Nature. 2016 Jul 21;535(7612):440-443. doi: 10.1038/nature18644. Epub 2016 Jul 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cellular Microenvironment / immunology
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Female
  • Gastrointestinal Microbiome / immunology
  • Immunity, Innate*
  • Immunity, Mucosal
  • Inflammation / immunology
  • Inflammation / metabolism
  • Interleukins / biosynthesis
  • Interleukins / immunology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology
  • Intestines / cytology
  • Intestines / immunology*
  • Lymphocytes / cytology
  • Lymphocytes / immunology*
  • Lymphocytes / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / metabolism
  • Neuroglia / immunology
  • Neuroglia / metabolism*
  • Neurotransmitter Agents / immunology
  • Neurotransmitter Agents / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-ret / deficiency
  • Proto-Oncogene Proteins c-ret / metabolism
  • STAT3 Transcription Factor / metabolism

Substances

  • Interleukins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Neurotransmitter Agents
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Proto-Oncogene Proteins c-ret
  • Ret protein, mouse
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • interleukin-22