Estrogen contributes to sex differences in M2-polarization during asthma

Abstract

Asthma is a chronic inflammation of the airways that affects over 300 million people worldwide. Asthma exhibits sex differences, affecting mostly boys in childhood and women in adulthood. Alveolar macrophages have emerged as major mediators of allergic lung inflammation. Macrophages express receptors that recognize and respond to estrogen. We hypothesized that estrogen enhances M2 polarization of alveolar macrophages and thereby contributes to asthma. We found increased expression of the canonical mouse M2 marker YM1 by alveolar macrophages from allergic female mice compared to male mice. Consistently, bone marrow derived macrophages (BMMs) from female mice exhibited higher levels of YM1 and ARG1 than did BMMs from male mice following stimulation with IL-4. This sex difference is reflected on the epigenetic level as M2 promoters in BMMs from female mice exhibited enhanced acetylated H3 compared to BMMs from male mice following stimulation with IL-4. Pretreatment of BMMs from female mice with estrogen receptor ligands enhanced IL-4-induced M2-gene expression. Using ovariectomized (OVx) and LysMCREERaflox/floxmice, we show that an absence of either estrogen or the estrogen receptor-a (ERa) impairs M2 polarization following challenge with OVA. Thus, macrophages exhibit sex differences in their ability to polarize to an M2-phenotype in vitro and in vivo. Estrogen and ERa engagement augment IL-4-induced M2-gene expression. Together these data suggest that sex and hormonal factors contribute to sex differences in macrophage responses during asthma. Understanding the role of estrogen signaling in M2-polarization is paramount for identifying novel therapeutic targets to better treat women with asthma.