Unexpected role for androgen and androgen receptor as enhancers of M2 macrophage polarization

Abstract

Abstract Allergic asthma is an inappropriate Th2 immune response in the lungs to innocuous inhaled antigens. This results in M2 polarization of alveolar macrophages (AM), which number correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Since estrogen enhances M2 polarization and androgens have been used as experimental asthma therapy, we hypothesized that androgens [testosterone and dihydrotestosterone (DHT)] and androgen receptor (AR) suppress M2 macrophage polarization. Here, we demonstrate that although androgen reconstitution in castrated mice reduced inflammation of the bronchoalveolar space in a mouse model of allergic lung inflammation, it enhanced the production of the eosinophil-recruiter and M2 marker YM1 in AM, indicating a cell-specific role for androgens. DHT also enhanced IL-4-induced M2 macrophage polarization in vitro. Using mice lacking the AR in monocytes/macrophages (ARfloxLysMCre), we found that ARfloxLysMCre males had less eosinophil recruitment and lung inflammation in our model of allergic lung inflammation. No differences were found in females. This decreased inflammation was due to impaired M2 polarization and diminished production of eosinophil-recruiting chemokines by AM rather to a regulatory profile of AM lacking AR. Furthermore, macrophages lacking AR did not show an increase in IL-4-induced M2 polarization in vitro with DHT treatment. These data reveal an unexpected role for androgen/AR in promoting M2 macrophage polarization, and suggest possible mechanisms to counteract diseases that are promoted by M2 macrophages and affect mainly men, such as eosinophilic esophagitis and prostate cancer.