An Interleukin-23-Interleukin-22 Axis Regulates Intestinal Microbial Homeostasis to Protect from Diet-Induced Atherosclerosis

Immunity. 2018 Nov 20;49(5):943-957.e9. doi: 10.1016/j.immuni.2018.09.011. Epub 2018 Oct 30.

Abstract

Although commensal flora is involved in the regulation of immunity, the interplay between cytokine signaling and microbiota in atherosclerosis remains unknown. We found that interleukin (IL)-23 and its downstream target IL-22 restricted atherosclerosis by repressing pro-atherogenic microbiota. Inactivation of IL-23-IL-22 signaling led to deterioration of the intestinal barrier, dysbiosis, and expansion of pathogenic bacteria with distinct biosynthetic and metabolic properties, causing systemic increase in pro-atherogenic metabolites such as lipopolysaccharide (LPS) and trimethylamine N-oxide (TMAO). Augmented disease in the absence of the IL-23-IL-22 pathway was mediated in part by pro-atherogenic osteopontin, controlled by microbial metabolites. Microbiota transfer from IL-23-deficient mice accelerated atherosclerosis, whereas microbial depletion or IL-22 supplementation reduced inflammation and ameliorated disease. Our work uncovers the IL-23-IL-22 signaling as a regulator of atherosclerosis that restrains expansion of pro-atherogenic microbiota and argues for informed use of cytokine blockers to avoid cardiovascular side effects driven by microbiota and inflammation.

Keywords: IL-22; IL-23; atherosclerosis; cytokines; host-microbe interaction; inflammation; microbiome; myeloid cells.

Publication types

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

MeSH terms

  • Animals
  • Atherosclerosis / etiology*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Biomarkers
  • Diet*
  • Disease Models, Animal
  • Disease Progression
  • Gastrointestinal Microbiome*
  • Gene Expression
  • Homeostasis*
  • Immunophenotyping
  • Interleukin-23 / deficiency
  • Interleukin-23 / metabolism*
  • Interleukins / metabolism*
  • Lipid Metabolism
  • Mice
  • Mice, Knockout
  • Osteopontin / genetics
  • Osteopontin / metabolism
  • Signal Transduction

Substances

  • Biomarkers
  • Interleukin-23
  • Interleukins
  • Osteopontin
  • interleukin-22