STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis

Cell Rep. 2017 Dec 26;21(13):3873-3884. doi: 10.1016/j.celrep.2017.11.101.

Abstract

Intestinal immune homeostasis is preserved by commensal bacteria interacting with the host to generate a balanced array of cytokines that are essential for wound repair and for combatting infection. Inflammatory bowel disease (IBD), which can lead to colitis-associated cancer (CAC), is thought to involve chronic microbial irritation following a breach of the mucosal intestinal epithelium. However, the innate immune pathways responsible for regulating these inflammatory processes remain to be fully clarified. Here, we show that commensal bacteria influence STING signaling predominantly in mononuclear phagocytes to produce both pro-inflammatory cytokines as well as anti-inflammatory IL-10. Enterocolitis, manifested through loss of IL-10, was completely abrogated in the absence of STING. Intestinal inflammation was less severe in the absence of cGAS, possibly suggesting a role for cyclic dinucleotides (CDNs) indirectly regulating STING signaling. Our data shed insight into the causes of inflammation and provide a potential therapeutic target for prevention of IBD.

Keywords: CAC; IBD; IL-10; STING; colitis-associated cancer; inflammatory bowel disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Lineage
  • Colitis / metabolism*
  • Colitis / pathology*
  • Colonic Polyps / metabolism
  • Colonic Polyps / pathology
  • Host-Pathogen Interactions
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Interleukin-10 / metabolism*
  • Membrane Proteins / deficiency
  • Membrane Proteins / metabolism*
  • Mice, Knockout
  • Models, Biological
  • Monocytes / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Signal Transduction

Substances

  • Membrane Proteins
  • Myeloid Differentiation Factor 88
  • Sting1 protein, mouse
  • Interleukin-10