T cell-derived IL-22 amplifies IL-1β-driven inflammation in human adipose tissue: relevance to obesity and type 2 diabetes

Diabetes. 2014 Jun;63(6):1966-77. doi: 10.2337/db13-1511. Epub 2014 Feb 11.

Abstract

Proinflammatory cytokines are critically involved in the alteration of adipose tissue biology leading to deterioration of glucose homeostasis in obesity. Here we show a pronounced proinflammatory signature of adipose tissue macrophages in type 2 diabetic obese patients, mainly driven by increased NLRP3-dependent interleukin (IL)-1β production. IL-1β release increased with glycemic deterioration and decreased after gastric bypass surgery. A specific enrichment of IL-17- and IL-22-producing CD4(+) T cells was found in adipose tissue of type 2 diabetic obese patients. Coculture experiments identified the effect of macrophage-derived IL-1β to promote IL-22 and IL-17 production by human adipose tissue CD4(+) T cells. Reciprocally, adipose tissue macrophages express IL-17 and IL-22 receptors, making them sensitive to IL-17 and IL-22. IL-22 increased IL-1β release by inducing pro-IL-1β transcription through activation of C-Jun pathways in macrophages. In sum, these human data identified IL-1β and the T-cell cytokine IL-22 as key players of a paracrine inflammatory pathway previously unidentified in adipose tissue, with a pathological relevance to obesity-induced type 2 diabetes. These results provide an additional rationale for targeting IL-1β in obesity-linked type 2 diabetes and may have important implications for the conception of novel combined anti-IL-1β and anti-IL-22 immunotherapy in human obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / pathology
  • Adult
  • Blotting, Western
  • Cell Line
  • Coculture Techniques
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Female
  • Gene Amplification
  • Glycated Hemoglobin A
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology*
  • Insulin Resistance* / genetics
  • Interleukin-1beta / metabolism*
  • Interleukins / metabolism*
  • Male
  • Obesity / genetics
  • Obesity / metabolism*
  • Real-Time Polymerase Chain Reaction
  • T-Lymphocytes / metabolism

Substances

  • Glycated Hemoglobin A
  • Interleukin-1beta
  • Interleukins
  • hemoglobin A1c protein, human
  • interleukin-22