Estrogen receptor α aggravates intestinal inflammation via promoting the activation of NLRP3 inflammasome

Activation of the NLRP3 inflammasome and Estrogen Receptor α (ERα) has been shown to increase the risk of inflammatory bowel diseases (IBD) or promote disease recurrence. In previous work, we demonstrated that ERα regulated the transcription of NLRP3. However, the precise mechanism by which ERα modulates NLRP3 in IBD models remains unclear. In this study, we induced IBD in wild-type mice using DSS or TNBS, followed by treatment with the ERα-specific agonist PPT. The results showed that IBD symptoms and intestinal inflammation responses were significantly exacerbated after PPT treatment. Furthermore, the activation of ERα by PPT led to a marked increase in the expression of NLRP3 and pro-inflammatory cytokines, including IL-1β and IL-18, suggesting that ERα activation exacerbated intestinal inflammation and impaired mucosal healing during the recovery phase of inflammation. In contrast, ERα-knockout mice exhibited only mild symptoms when exposed to DSS or TNBS, with a concurrent reduction in NLRP3 expression, indicating that ERα plays a role in inflammation susceptibility. Similar findings were observed in NCM-460 cells, where the inflammation response was attenuated in ERα-knockdown cells. Importantly, we demonstrated that ERα interacted with the NLRP3 inflammasome and promoted its assembly. Collectively, we propose an underlying pathogenesis of IBD, that is, ERα can interact with the NLRP3 inflammasome and promote its expression and assembly, thereby exacerbating intestinal inflammation in IBD models. Therefore, ERα could serve as a potential therapeutic target for NLRP3 inflammasome-associated intestinal inflammation.

ERα-knockout mice; ERα-specific agonist; Estrogen receptor α; Inflammatory bowel diseases; Intestinal epithelial cells; NLRP3 inflammasome.