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

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 (11)-1 beta production. IL-1 beta 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-1 beta to promote IL-22 and IL-17 production by human adipose tissue CDC4+ 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-1 beta release by inducing pro-IL-1 beta transcription through activation of C-Jun pathways in macrophages. In sum, these human data identified IL-1 beta 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-1 beta in obesity-linked type 2 diabetes and may have important implications for the conception of novel combined anti-IL-1 beta and anti-IL-22 immunotherapy in human obesity.