MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, Jiangsu Province, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113425. doi: 10.1016/j.intimp.2024.113425. Epub 2024 Oct 19.
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.
NLRP3 炎性小体和雌激素受体 α（ERα）的激活已被证明会增加炎症性肠病（IBD）的风险或促进疾病复发。在之前的工作中，我们证明了 ERα 调节 NLRP3 的转录。然而，ERα 在 IBD 模型中调节 NLRP3的确切机制仍不清楚。在这项研究中，我们使用 DSS 或 TNBS 诱导野生型小鼠发生 IBD，然后用 ERα 特异性激动剂 PPT 进行治疗。结果表明，PPT 处理后 IBD 症状和肠道炎症反应明显加重。此外，PPT 激活 ERα 导致 NLRP3 和促炎细胞因子（包括 IL-1β 和 IL-18）的表达显著增加，表明 ERα 激活在炎症恢复阶段加剧了肠道炎症并损害了黏膜愈合。相比之下，当暴露于 DSS 或 TNBS 时，ERα 敲除小鼠仅表现出轻微的症状，同时 NLRP3 的表达减少，表明 ERα 在炎症易感性中发挥作用。在 NCM-460 细胞中也观察到了类似的发现，其中 ERα 敲低细胞的炎症反应减弱。重要的是，我们证明 ERα 与 NLRP3 炎性小体相互作用并促进其组装。综上所述，我们提出了 IBD 的潜在发病机制，即 ERα 可以与 NLRP3 炎性小体相互作用并促进其表达和组装，从而加剧 IBD 模型中的肠道炎症。因此，ERα 可能成为 NLRP3 炎性小体相关肠道炎症的潜在治疗靶点。
