Modulation of monocyte heterogeneity and macrophage polarization through estrogenic pathways

The inflammatory response, particularly M1 and M2 macrophages, are involved in the development of cardiometabolic disease. During their reproductive years, women are generally protected from disease events by their estrogen-replete status. We set out to understand these estrogen-dependent effects in mouse monocytes and cultured human monocyte-derived macrophages. In estrogen-receptor-α knockout mice, a significant fall in alternatively activated “M2” Ly6Clow/CX3CR1+ circulating monocytes was observed compared with wild-type. Resting human monocyte-derived macrophages display a predominant M2 phenotype. Upon M1 polarization with LPS/IFNγ, the resulting M2 to M1 surface antigen shift was associated with intracellular TNF-α production. This was prevented by overnight incubation with 17β-estradiol and short-term (45-min) incubation with the GPER-1 agonist G1. In addition, 17β-estradiol enhanced the upregulation of M2 CD163 and CD206 antigens induced by IL-4/IL-13. Understanding the immunophenotype of monocyte/macrophages in ageing women in relation to estrogen levels may assist in identifying potential pharmacological targets against disease.