Estradiol conjugation to estrogen receptorα upregulates Brms1 expression mediating M2 polarization of alveolar macrophages and exacerbating airway inflammation in asthmatic mice

Abstract

Asthma is a common condition involving chronic airway inflammation that primarily affects women and boys. Estrogen levels correlate with the observed differences in the prevalence of asthma between the sexes, but the exact mechanism is unclear. This study established a castration mice (OVX) model through bilateral ovariectomy surgery, and subcutaneously injected estradiol (E2) into OVX asthmatic mice to analyze the effect of E2 on the onset of asthma. Then, airway inflammation was evaluated in the mice using airway resistance measurements, lung tissue hematoxylin and eosin staining, and eosinophil counts. Furthermore, the proportion of CD206-positive cells and the expression of M2 polarization markers, such as Arg1 and YM1, were detected in alveolar macrophages (AMs). The effects of different concentrations of E2 on M2 polarization of AMs were examined in vitro, and the types of estrogen receptors (ERs) involved were investigated. Transcriptome analysis combined with volcano plots and heatmaps were used to compare the differentially expressed genes to investigate the mechanism by which E2 affects M2 polarization of AMs. The results showed that female asthmatic mice had more severe airway inflammation and higher airway responsiveness than male asthmatic mice. E2 increased airway inflammation and airway resistance in asthmatic mice. E2 not only promoted M2 polarization of AMs in asthmatic mice in vivo, but also increased the expression of M2 markers, such as Arg1 and YM1, by AMs in vitro. The use of ERα antagonist AZD9496 reduced the effect of E2 on the promotion of M2 polarization in AMs. Analysis of transcriptome differences indicated that E2 upregulated expression of M2 breast cancer metastasis suppressor gene 1 (Brms1) in AMs. Notably, antagonism of ERα inhibited this upregulation of Brms1 gene expression. Interference with Brms1 mRNA production reduced the gene expression of Arg1 and YM1 in AMs undergoing M2 polarization after E2 stimulation. In summary, E2 exacerbates airway inflammation in asthmatic mice and binds to ERα, upregulating Brms1 expression and mediating M2 polarization of AMs.