Caspase-10 affects the pathogenesis of primary biliary cholangitis by regulating inflammatory cell death

• Published in: Journal of autoimmunity 2022-12, Vol.133, p.102940-102940, Article 102940
• Main 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
• Format: Article
• Language: English
• Subjects: Autoimmunity; Caspase-10; Exome sequencing; Inflammatory cell death; Primary biliary cholangitis
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2022.102940

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. [Display omitted] •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.