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

 Minjeong Cho  ;  So Hee Dho  ;  Saeam Shin  ;  Yeongun Lee  ;  Yoonjung Kim  ;  Jiyeon Lee  ;  Su Jong Yu  ;  Sang Hoon Park  ;  Kyung-A Lee  ;  Lark Kyun Kim 
 JOURNAL OF AUTOIMMUNITY, Vol.133 : 102940, 2022-12 
Journal Title
Issue Date
Caspase 10 ; Caspase 8 / genetics ; Cell Death / genetics ; Female ; Humans ; Liver Cirrhosis, Biliary* / genetics
Autoimmunity ; Caspase-10 ; Exome sequencing ; Inflammatory cell death ; Primary biliary cholangitis
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Lark Kyun(김락균) ORCID logo https://orcid.org/0000-0001-5983-4470
Kim, Yoon Jung(김윤정) ORCID logo https://orcid.org/0000-0002-4370-4265
Dho, So Hee(도소희) ORCID logo https://orcid.org/0000-0001-7343-713X
Shin, Saeam(신새암) ORCID logo https://orcid.org/0000-0003-1501-3923
Lee, Kyung A(이경아) ORCID logo https://orcid.org/0000-0001-5320-6705
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