Estrogen contributes to sex differences in M2-polarization during asthma

Abstract

Asthma is a chronic inflammation of the airways that exhibits sex differences, affecting mostly boys in childhood and women in adulthood. Alveolar macrophages have emerged as major mediators of allergic lung inflammation. We hypothesized that alveolar macrophages respond to estrogen by enhancing M2 responses and thereby contribute to sex differences in asthma. We found that macrophages from female mice exhibited increased expression of canonical M2 markers like Ym1 and Arg1 in response to IL-4. Signaling through ERα further enhanced IL-4-induced M2 gene expression in macrophages from female mice. The promoters of these genes contained increased abundance of transcriptionally active modifications like H3Ac and H3K4Me3 in macrophages from female mice. Using an OVA model of allergic lung inflammation, we found that female mice exhibited enhanced M2-polarization in vivo after allergen challenge. M2-polarization was impaired in ovariectomized (OVx) mice and but was restored with estrogen replacement. Further, we established a mixed bone marrow chimera model whereby irradiated mice were reconstituted with a 1:1 mix of bone marrow from CD45.1+ WT and CD45.2+ LysMCREERαflox/flox mice. In these mice, ERα-sufficient alveolar macrophages exhibited enhanced M2-polarization compared to ERα−/− alveolar macrophages. ERα−/−cells were largely retained in the bone marrow, suggesting that E2 regulates leukocyte trafficking during lung inflammation. 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.