Adipocyte-Secreted IL-6 Sensitizes Macrophages to IL-4 Signaling

Abstract

Complex bidirectional cross talk between adipocytes and adipose tissue immune cells plays an important role in reg-ulating adipose function, inflammation, and insulin respon-siveness. Adipocytes secrete the pleiotropic cytokine IL-6 in response to both inflammatory and catabolic stimuli. Previous studies have suggested that IL-6 secretion from adipocytes in obesity may promote adipose tissue inflam-mation. Here, we investigated catabolic stimulation of adi-pocyte IL-6 secretion and its impact on adipose tissue immune cells. 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. We report that in this con-text, adipocyte-secreted IL-6 activates local macrophage STAT3 to promote Il4ra expression, thereby sensitizing them to IL-4 signaling and promoting an anti-inflammatory gene expression pattern. Supporting a paracrine adipo-cyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pre-treat bone marrow–derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in adipose tissue are complex and context specific. These results suggest that cAMP-driven IL-6 secretion from adipocytes sensitizes adipose tissue macrophages to IL-4 signaling.