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

Yu-Wen Wang; Chia-I Lin; Hung-Wen Chen; Jui-Ching Wu; Ya-Hui Chuang

doi:10.1016/j.jtauto.2022.100182

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

J Transl Autoimmun. 2022 Dec 21:6:100182. doi: 10.1016/j.jtauto.2022.100182. eCollection 2023.

Authors

Yu-Wen Wang¹, Chia-I Lin¹, Hung-Wen Chen¹, Jui-Ching Wu^{1

2}, Ya-Hui Chuang^{1

2}

Affiliations

¹ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.

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.

Keywords: 2-OA, 2-octynoic acid; 2-OA-OVA, 2-octynoic acid conjugated ovalbumin; AIC, autoimmune cholangitis; AMAs, anti-mitochondrial antibodies; Apoptosis; Autoimmune cholangitis; BECs, biliary epithelial cells; Gut microbiota; PBC, primary biliary cholangitis; PDC-E2, E2 component of pyruvate dehydrogenase complex; TLR, toll-like receptor; TUNEL, TdT-mediated deoxyuridine triphosphate nick-end labeling; Toll-like receptor; Xenobiotic.