Estrogen receptor β activation ameliorates DSS-induced chronic colitis by inhibiting inflammation and promoting Treg differentiation

Estrogen receptor (ER) β activation has anti-inflammatory activity. However, its effect on the development of inflammatory bowel disease (IBD) and the underlying mechanism have not been clarified. This study aimed to assess the clinical value of ERβ+CD4+ T cells in IBD patients and examine the anti-inflammatory role of ERβ activation in dextran sulfate sodium (DSS)-induced chronic colitis in mice. We investigated the effects of ERB041 (an ERβ-specific agonist) on inflammatory cytokines and pro-inflammatory T-cell and regulatory T-cell (Treg) responses in murine colitis. We tested the role of ERβ activation on Treg differentiation and its activity to suppress T-cell proliferation in vitro. We found that reduced frequency of circulating ERβ+CD4+ T cells in IBD patients was negatively correlated with inflammation and disease severity. ERβ and FoxP3 expression co-localized in the intestinal tissues of IBD patients. Treatment with ERB041 significantly mitigated colitis-induced weight loss, inflammation, and disease severity. It also restored the ERβ+CD4+ T cell population in the spleen and colon lamina propria of these mice. ERB041 treatment inhibited CD4+CD25- and CD8+ T cell infiltration and restored Tregs and activated T-cell immunoreceptor with Ig and ITIM domains (TIGIT)+ Tregs in the colon lamina propria. In vitro, we found that ERβ activation enhanced Treg differentiation, immunosuppression, and TGF-β1/Smad signaling in CD4+ T cells. Our data suggest that ERβ+CD4+ T cells represent a potential biomarker for evaluating IBD disease severity, and ERβ activation may be valuable for the treatment of IBD by enhancing the Treg response.