背景:肠道纤维化,结肠炎的复杂并发症,其特征在于过度的细胞外基质(ECM)沉积。雌激素受体(ER)β可能在调节这一过程中起作用。
方法:从克罗恩病(CD)患者收集狭窄和非狭窄区域的肠组织样本。在小鼠模型上进行RNA测序以鉴定差异表达的mRNA。组织学,免疫组织化学,和半定量Western印迹分析用于评估ECM沉积和纤维化。相关通路在成纤维细胞转分化中的作用,活动,和迁移进行了检查。
结果:发现CD患者狭窄的肠组织中雌激素受体β的表达下调。组织学纤维化评分,胶原蛋白沉积,肠纤维化小鼠模型的结肠中的促纤维化分子在激活ERβ后显著降低。体外,ERβ激活减轻转化生长因子(TGF)-β诱导的成纤维细胞活化和迁移,如抑制co1α1,纤连蛋白,α-平滑肌肌动蛋白(α-SMA),胶原蛋白I,和N-钙粘蛋白表达。RNA测序显示ERβ激活影响ECM稳态和组织重塑相关基因的表达。差异表达基因的富集分析强调下调基因在ECM-受体相互作用中富集,TGF-β信号,和Toll样受体(TLR)信号。Western印迹证实TGF-β/Smad和TLR4/MyD88/NF-κB信号通路参与体内和体外调节纤维化。TGF-β1和TLR4的启动子活性可被ERβ转录因子抑制。
结论:雌激素受体β可能通过调节TGF-β/Smad和TLR4/MyD88/NF-κB信号通路调控肠纤维化。靶向ERβ激活可能是治疗肠纤维化的有希望的治疗策略。
想象一下你的肠子就像一根花园软管。在克罗恩病中,这个“软管”的部分变得狭窄和阻塞。科学家发现一种有用的蛋白质较少,ERβ,在这些狭窄的区域。在老鼠的实验中,增强ERβ减少了肠道损伤并减少了胶原蛋白的积累-这是我们软管类比中的“阻塞”。此外,ERβ使过度活跃的细胞引起这些问题,表现得像个和事佬.这种蛋白质通过称为TGF-β/Smad和TLR4/NF-κB的通道与细胞“对话”,告诉他们放松。这可能是解决这种肠道问题的新方法!
BACKGROUND: Intestinal fibrosis, a complex complication of colitis, is characterized by excessive extracellular matrix (ECM) deposition. Estrogen receptor (ER) β may play a role in regulating this process.
METHODS: Intestinal tissue samples from stenotic and nonstenotic regions were collected from Crohn\'s disease (CD) patients. RNA sequencing was conducted on a mouse model to identify differentially expressed mRNAs. Histological, immunohistochemical, and semiquantitative Western blotting analyses were employed to assess ECM deposition and fibrosis. The roles of relevant pathways in fibroblast transdifferentiation, activity, and migration were examined.
RESULTS: Estrogen receptor β expression was found to be downregulated in the stenotic intestinal tissue of CD patients. Histological fibrosis score, collagen deposition, and profibrotic molecules in the colon of an intestinal fibrosis mouse model were significantly decreased after activation of ERβ. In vitro, ERβ activation alleviated transforming growth factor (TGF)-β-induced fibroblast activation and migration, as evidenced by the inhibition of col1α1, fibronectin, α-smooth muscle actin (α-SMA), collagen I, and N-cadherin expression. RNA sequencing showed that ERβ activation affected the expression of genes involved in ECM homeostasis and tissue remodeling. Enrichment analysis of differentially expressed genes highlighted that the downregulated genes were enriched in ECM-receptor interaction, TGF-β signaling, and Toll-like receptor (TLR) signaling. Western blotting confirmed the involvement of TGF-β/Smad and TLR4/MyD88/NF-κB signaling pathways in modulating fibrosis both in vivo and in vitro. The promoter activity of TGF-β1 and TLR4 could be suppressed by ERβ transcription factor.
CONCLUSIONS: Estrogen receptor β may regulate intestinal fibrosis through modulation of the TGF-β/Smad and TLR4/MyD88/NF-κB signaling pathways. Targeting ERβ activation could be a promising therapeutic strategy for treating intestinal fibrosis.
Imagine your gut is like a garden hose. In Crohn’s disease, parts of this “hose” get narrow and blocked. Scientists found less of a helpful protein, ERβ, in these narrow areas. In an experiment with mice, boosting ERβ lessened the gut damage and reduced the buildup of collagen—the “blockage” in our hose analogy. Also, ERβ calmed overactive cells causing these issues, acting like a peacemaker. This protein “talks” to cells through channels called TGF-β/Smad and TLR4/NF-κB, telling them to relax. This could be a new way to tackle such gut problems!