The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity

Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the other hand, recombinant IL-9 (rIL-9) treatment reversed insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and insulin tolerance, defective insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELMα+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1β and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves insulin signaling by inhibiting NLRP3-induced inflammation.