IL-13Rα2 modulates inflammatory and metabolic effects of IL-33 by regulation of tissue IL-13 responses

Abstract In experimental models of obesity, IL-13 can overcome insulin resistance by promoting eosinophilic inflammation and M2 macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine, and by IL-33, which triggers release of IL-13. We propose that elevation of tissue IL-13 levels resulting from IL-13Rα2 deficiency, with or without IL-33 administration, counteracts the metabolic stress of obesity produced by a high fat diet. IL-13Rα2 expression was found to be elevated in adipose tissue of obese mice. Mice deficient in IL-13Rα2 had high expression of M2 markers in adipose tissue, consistent with increased IL-13 activity. IL-33 administration raised serum and tissue IL-13 concentrations, produced splenomegaly, elevated tissue eosinophils, macrophages, and ILC2s, and induced an inflammatory gene expression signature in adipose tissue. IL-33 reduced body weight, adipocyte size and fasting blood glucose to a greater extent in IL-13Rα2-deficient mice compared to wild-type littermates, and these changes were attenuated in mice lacking IL-13. In contrast, IL-33-induced splenomegaly and eosinophilia were exacerbated in the absence of IL-13, associated with impaired induction of the soluble decoy receptor, ST2, and unrestrained IL-33 activity. In the context of high fat diet, IL-33 administration resulted in damaging systemic inflammation, which was enhanced in IL-13Rα2-deficient mice. These findings suggest that IL-13Rα2 regulation of tissue IL-13 levels can result in a skewed M2 bias under conditions of metabolic stress, and implicate IL-13Rα2 as a critical checkpoint to limit adverse effects of the IL-33/IL-13 axis.