Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling

Abstract

Complex bidirectional crosstalk between adipocytes and adipose tissue immune cells plays an important role in regulating adipose function, inflammation, and insulin responsiveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies suggest that IL-6 secretion from adipocytes in obesity promotes adipose tissue inflammation. Here we investigated catabolic stimulation of adipocyte IL-6 secretion and its impact on adipose tissue inflammation. In obesity, catecholamine resistance reduces cAMP-driven adipocyte IL-6 secretion in response to catabolic signals. By restoring adipocyte catecholamine sensitivity in obese adipocytes, amlexanox stimulates adipocyte-specific IL-6 secretion. Here we report that in this context, adipocyte secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling, and promoting a more anti-inflammatory phenotype. Supporting a paracrine adipocyte to macrophage mecnaism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow derived macrophages prior to polarization with IL-4. This cross talk may contribute to reduction in adipose tissue inflammation observed with amlexanox treatment in vivo. The effects of IL-6 signaling in the adipose tissue are complex and context specific. These results suggest that restoration of cAMP driven IL-6 secretion from obese adipocytes may reduce adipose tissue inflammation.Graphic abstract