Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages

Science. 2017 May 5;356(6337):513-519. doi: 10.1126/science.aal3535.

Abstract

Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays a critical role in the control of immune responses. However, its mechanisms of action remain poorly understood. Here, we show that IL-10 opposes the switch to the metabolic program induced by inflammatory stimuli in macrophages. Specifically, we show that IL-10 inhibits lipopolysaccharide-induced glucose uptake and glycolysis and promotes oxidative phosphorylation. Furthermore, IL-10 suppresses mammalian target of rapamycin (mTOR) activity through the induction of an mTOR inhibitor, DDIT4. Consequently, IL-10 promotes mitophagy that eliminates dysfunctional mitochondria characterized by low membrane potential and a high level of reactive oxygen species. In the absence of IL-10 signaling, macrophages accumulate damaged mitochondria in a mouse model of colitis and inflammatory bowel disease patients, and this results in dysregulated activation of the NLRP3 inflammasome and production of IL-1β.

Publication types

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

MeSH terms

  • Animals
  • Colitis / immunology*
  • Disease Models, Animal
  • Humans
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Inflammatory Bowel Diseases / immunology*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Interleukin-1beta / metabolism
  • Intestines / immunology*
  • Macrophages / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Interleukin-10 / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism

Substances

  • DDIT4 protein, human
  • IL10 protein, human
  • IL10 protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • Receptors, Interleukin-10
  • Transcription Factors
  • Interleukin-10
  • MTOR protein, human
  • TOR Serine-Threonine Kinases