American Diabetes Association
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Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling

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posted on 2022-11-30, 15:34 authored by Danny Luan, Benyamin Dadpey, Jessica Zaid, Pania E. Bridge-Comer, Julia H. DeLuca, Wenmin Xia, Joshua Castle, Shannon M. Reilly

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 may promote adipose tissue inflammation. Here we investigated catabolic stimulation of adipocyte 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. 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 an anti-inflammatory gene expression pattern. Supporting a paracrine adipocyte to macrophage mechanism, these effects could be recapitulated using adipocyte conditioned media to pretreat bone marrow derived macrophages prior to polarization with IL-4. The effects of IL-6 signaling in the 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.


This work was supported by the US National Institutes of Health grants R01DK126944 to S.M.R., This work was also supported by the American Diabetes Association grant 1-19-JDF-012 to S.M.R. D.L. was also supported by the University of Michigan Undergraduate Research Opportunity Program Summer Biomedical and Life Sciences Fellowship. J.C. was supported by the Perrigo Undergraduate Summer Fellowship. W.X. was supported by the Austrian Science Fund FWF SFB LIPTOX F3018, P27108, P28882, DK-MCD W1226 and Austrian Marshall Plan Scholarship.


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