T Cell–Derived IL-22 Amplifies IL-1β–Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes

  1. Michèle Guerre-Millo1,2,3,4
  1. 1INSERM, UMR-S 1166 and 1138, Paris, France
  2. 2Sorbonne Universités, Pierre et Marie Curie-Paris6, Paris, France
  3. 3Université Paris Descartes, Paris, France
  4. 4Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
  5. 5Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department, Paris, France
  1. Corresponding authors: Michèle Guerre-Millo, michele.guerre-millo{at}crc.jussieu.fr, and Elise Dalmas, elise.dalmas{at}unibas.ch.
  1. S.A. and M.G.-M. contributed equally to this study.

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.

Footnotes

  • Received October 1, 2013.
  • Accepted February 3, 2014.

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  1. Diabetes vol. 63 no. 6 1966-1977
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