Apoptotic biliary epithelial cells and gut dysbiosis in the induction of murine primary biliary cholangitis

IF 4.7 Q2 IMMUNOLOGY
Yu-Wen Wang , Chia-I Lin , Hung-Wen Chen , Jui-Ching Wu , Ya-Hui Chuang
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引用次数: 4

Abstract

Primary biliary cholangitis (PBC) is a female-predominant liver autoimmune disease characterized by the specific immune-mediated destruction of the intrahepatic small bile duct. Although apoptosis of biliary epithelial cells (BECs) and alterations in gut microbiota are observed in patients with PBC, it is still unclear whether these events happen in the early stage and cause the breakdown of tolerance in PBC. In this study, we examined the early events in the loss of tolerance in our well-defined 2-OA-OVA-induced murine autoimmune cholangitis (AIC) model. We report herein that apoptosis of BECs was notable in the early stage of murine AIC. An altered gut microbiota, in particular, an increased percentage of gram-positive Firmicutes in AIC mice was also observed. BECs in AIC mice expressed adhesion molecule ICAM-1, cytokines/chemokines TNF-α, CCL2, CXCL9, CXCL10, and toll-like receptor (TLR) 2. Moreover, BECs treated with TLR2 ligand had elevated apoptosis and CXCL10 production. These data collectively suggest a new mechanism of tolerance breakdown in AIC. Altered gut microbiota induces apoptosis of BECs through TLR2 signaling. BECs secrete chemokines to recruit CD8 T cells to damage BECs further.

Abstract Image

Abstract Image

Abstract Image

小鼠原发性胆道胆管炎诱导的胆道上皮细胞凋亡和肠道生态失调
原发性胆管炎(PBC)是一种以女性为主的肝脏自身免疫性疾病,其特征是特异性免疫介导的肝内小胆管破坏。尽管在PBC患者中观察到胆道上皮细胞(BECs)的凋亡和肠道微生物群的改变,但尚不清楚这些事件是否发生在早期并导致PBC耐受性的破坏。在这项研究中,我们在定义明确的2- oa - ova诱导的小鼠自身免疫性胆管炎(AIC)模型中检查了耐受性丧失的早期事件。我们在此报道,BECs凋亡在小鼠AIC的早期阶段是显著的。还观察到AIC小鼠肠道微生物群的改变,特别是革兰氏阳性厚壁菌门的百分比增加。AIC小鼠的BECs表达粘附分子ICAM-1、细胞因子/趋化因子TNF-α、CCL2、CXCL9、CXCL10和toll样受体(TLR) 2。此外,TLR2配体处理的BECs细胞凋亡和CXCL10的产生升高。这些数据共同提示了一种新的AIC耐受性分解机制。肠道菌群改变通过TLR2信号通路诱导BECs凋亡。BECs分泌趋化因子募集CD8 T细胞进一步损伤BECs。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Translational Autoimmunity
Journal of Translational Autoimmunity Medicine-Immunology and Allergy
CiteScore
7.80
自引率
2.60%
发文量
33
审稿时长
55 days
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