Sex Differences in Human Monocyte/Macrophages in Response to IL‐4
Authors: Diaz Mireya Becerra , Heller Nicola M 
Published: June 2021

BackgroundAllergic asthma is a common chronic inflammatory disease of the lungs that affects 10% of the population in developed countries. Asthma shows a sex difference with more boys than girls diagnosed before puberty. In adulthood, women are twice as likely to have asthma than men. Women can also have increased disease severity and be less responsive to corticosteroid treatment. Sex hormones therefore may be important in asthma. Asthmatics have more and a greater percentage of M2 macrophages in their lungs than healthy individuals. Mouse studies have also demonstrated that M2 macrophages contribute to worse allergic lung inflammation. Furthermore, estrogen (E2) stimulates the production of M2 macrophage‐related cytokines that promote lung remodeling. How sex steroids affect monocyte‐macrophages to enhance M2 polarization is still unknown.Aim of the studyTo determine the molecular basis of sex differences and E2/androgen modulation of IL‐4‐induced M2 macrophage differentiation.ResultsOur preliminary data showed that both human monocytes and monocyte derived‐macrophages (MDM) from asthmatic donors upregulated M2 genes (CCL22, CCL17, TGM2, and MMP12) than cells from healthy donors, on IL‐4 stimulation. Moreover, expression of CCL17, TGM2, and CD200R was higher in MDM from asthmatic donors than in monocytes. IL‐4‐induced CCL17 and MMP12 shown a trend to greater expression in asthmatic female than male MDM. To explain the differences in IL‐4 responsiveness, we measured IL‐4 receptors (IL‐4R) on monocytes from men and women. Expression of γC, part of the type‐I IL‐4R complex, was greater on the surface of monocytes from healthy female compared to male donors. Conversely, IL‐13Rα2, an inhibitory receptor for IL‐13, was higher on male monocytes. To determine how responsive macrophages may be to E2 stimulation, we quantified estrogen receptor (ER) expression in MDM from healthy and allergic donors. MDM from allergic donors expressed more mRNA for ERα and less ERβ (linked to inhibition of E2 responses) and AR compared with MDM from a healthy donor. These data match the increased expression of ERα we measured in alveolar macrophages from female mice compared to male mice during allergic lung inflammation. Expression of CD206 greater on IL‐4‐stimulated cells in the presence of E2, mirroring our findings of increased M2 gene expression in mouse macrophages treated with E2 in vitro and in ovariectomized female mice implanted with E2 in vivo.ConclusionsOur preliminary results suggest that MDM from asthmatic donors are more sensitive to IL‐4 with enhanced M2 polarization. Sex differences in IL‐4R expression suggest increased IL‐4/‐13 responsiveness in female compared to male monocytes. ERα expression is higher in allergic MDMs and likely promotes enhanced M2 phenotype in the presence of E2. E2 promoted M2 polarization in human and mouse macrophages. Understanding the differences in monocyte‐macrophage responses between women and men and the effect of sex steroids on asthma can lead to developing better therapies for asthma according to the sex of the patient.Support or Funding InformationNIH grant R01 HL124477This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.