Estrogen Signaling Contributes to Sex Differences in Macrophage Polarization during Asthma

Abstract

Allergic asthma is a chronic Th2 inflammation in the lungs that constricts the airways and presents as coughing and wheezing. Asthma mostly affects boys in childhood and women in adulthood, suggesting that shifts in sex hormones alter the course of the disease. Alveolar macrophages have emerged as major mediators of allergic lung inflammation in animal models as well as humans. Whether sex differences exist in macrophage polarization and the molecular mechanism(s) which drive differential responses are not well understood. We found that IL-4- stimulated bone marrow-derived and alveolar macrophages from female mice exhibited greater expression of M2 genes in vitro and after allergen challenge in vivo. Alveolar macrophages from female mice exhibited greater expression of the IL-4 receptor (IL-4R)-α and estrogen receptor (ER)-α compared to macrophages from male mice following allergen challenge. An ERα-specific agonist enhanced IL-4-induced M2 gene expression in macrophages from both sexes but more so in macrophages from female mice. Further, IL-4-stimulated macrophages from female mice exhibited more transcriptionally active histone modifications at M2 gene promoters than did macrophages from male mice. We found that supplementation of estrogen into ovariectomized female mice enhanced M2-polarization in vivo upon challenge with allergen and that macrophage-specific deletion of ERα impaired this M2-polarization. The effects of estrogen are long-lasting; bone marrow derived macrophages from ovariectomized mice implanted with estrogen exhibited enhanced IL-4-induced M2-gene expression compared to macrophages from placebo-implanted littermates. Taken together, our findings suggest that estrogen enhances IL-4-induced M2-gene expression and thereby contributes to sex differences observed in asthma.

Modulation of the lung inflammatory response to ozone by the estrous cycle

“…While studies in cells and animal models have addressed the contributions of male and female sex hormones to lung immunity (Keselman and Heller ; Keselman et al. ; Fuseini et al. ), only a few studies have addressed the mechanisms by which physiological hormonal fluctuations that occur in the female reproductive cycle affect the inflammatory response (Fuentes et al.…”

“…A few studies in cells and animal models have also shown that sex hormones can affect airway tone, inflammation, immune cell function, and transcription of specific genes that alter host immunity and promote immune cell proliferation (Chang and Mitzner 2007;Fuseini and Newcomb 2017;Yung et al 2018). While studies in cells and animal models have addressed the contributions of male and female sex hormones to lung immunity (Keselman and Heller 2015;Keselman et al 2017;Fuseini et al 2018), only a few studies have addressed the mechanisms by which physiological hormonal fluctuations that occur in the female reproductive cycle affect the inflammatory response Fuentes and Silveyra 2019).…”

Randomized controlled trial demonstrating the benefits of delta inulin adjuvanted immunotherapy in patients with bee venom allergy

“…This is consistent with female subjects, postmenarche, having a more T H 2-biased immune system, making them prone to allergy. 54 However, after 3 years of VIT, the female subjects in both groups had reduced specific IgE levels, indicating that VIT is effective irrespective of sex.…”

Oestrogen amplifies pre‐existing atopy‐associated Th2 bias in an experimental asthma model

“…Several experimental models have reported a host of immunological effects of E2 including a role in DC maturation, effects on CD103 + DC and macrophage polarization in the airways. Some of these effects are directly mediated through estrogen receptors that are expressed widely across cell populations in the immune system.…”