T Cell–Derived IL-22 Amplifies IL-1β–Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes
- Elise Dalmas1,2,3,4⇑,
- Nicolas Venteclef1,2,3,4,
- Charles Caer1,2,3,4,
- Christine Poitou1,2,3,4,5,
- Isabelle Cremer1,2,3,
- Judith Aron-Wisnewsky1,2,3,4,5,
- Sébastien Lacroix-Desmazes1,2,3,
- Jagadeesh Bayry1,2,3,
- Srinivas V. Kaveri1,2,3,
- Karine Clément1,2,3,4,5,
- Sébastien André1,2,3,4 and
- Michèle Guerre-Millo1,2,3,4⇑
- 1INSERM, UMR-S 1166 and 1138, Paris, France
- 2Sorbonne Universités, Pierre et Marie Curie-Paris6, Paris, France
- 3Université Paris Descartes, Paris, France
- 4Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Paris, France
- 5Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Nutrition and Endocrinology Department, Paris, France
- Corresponding authors: Michèle Guerre-Millo, , and Elise Dalmas, .
S.A. and M.G.-M. contributed equally to this study.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1511/-/DC1.
- Received October 1, 2013.
- Accepted February 3, 2014.
- © 2014 by the American Diabetes Association.
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