Caspase-10 affects the pathogenesis of primary biliary cholangitis by regulating inflammatory cell death. Issue 133 (December 2022)

• Record Type: Journal Article
• Authors: Cho, Minjeong; Dho, So Hee; Shin, Saeam; Lee, Yeongun; Kim, Yoonjung; Lee, Jiyeon; Yu, Su Jong; Park, Sang Hoon; Lee, Kyung-A; Kim, Lark Kyun
• Is Part Of: Journal of autoimmunity. Issue 133(2022)
• Publication Date: 2022-12
• Subjects: Primary biliary cholangitis -- Caspase-10 -- Autoimmunity -- Inflammatory cell death -- Exome sequencing; ALPS autoimmune lymphoproliferative syndrome -- CI confidence interval -- DED death-effector domain -- DEGs differentially expressed genes -- GSEA gene set enrichment analysis -- GWAS genome-wide association studies -- HSC hepatic stellate cell -- KO knockout -- OCA obeticholic acid -- OR odd ratio -- PCA principal component analysis -- PBC Primary biliary cholangitis -- UDCA ursodeoxycholic acid -- WES whole-exome sequencing; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2022.102940
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment. Graphical abstract: Image 1 Highlights: We identified 61 rare heterozygote variants in a multi-PBC patient family. Caspase-10 regulates inflammatory cell deaths more strongly than caspase-8. The caspase-10 deficiency affects the fibrotic response of hepatic stellate cells.