한빛사논문
- 조회426
Minjeong Choa1, So Hee Dhoa1, Saeam Shinb1, Yeongun Leea, Yoonjung Kimb, Jiyeon Leea, Su Jong Yuc, Sang Hoon Parkd, Kyung-A Leeb, Lark Kyun Kima
aSeverance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
bDepartment of Laboratory Medicine, Yonsei University College of Medicine, Seoul, South Korea
cDepartment of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
dDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea
1These authors contributed equally to this work.
Corresponding authors: Sang Hoon Park, Kyung-A Lee, Lark Kyun Kim
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.
논문정보
- Research article
- 2022년 10월 (BRIC 등록일 2022-11-07)
- 국내 연구진
- 생명과학 > 면역학
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