Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis

被引：36

作者：

Li, Xi ^{[1
,2
,3
]}

Li, Yan ^{[1
,2
]}

Xiao, Jintao ^{[1
,2
,4
]}

Wang, Huiwen ^{[1
,2
,5
]}

Guo, Yan ^{[1
,2
,6
]}

Mao, Xiuru ^{[1
,2
,5
]}

Shi, Pan ^{[1
,2
]}

Hou, Yanliang ^{[1
,2
,4
]}

Zhang, Xiaoxun ^{[1
,2
]}

Zhao, Nan ^{[1
,2
]}

Zheng, Minghua ^{[7
]}

He, Yonghong ^{[1
,2
]}

Ding, Jingjing ^{[1
,2
]}

Tan, Ya ^{[1
,2
]}

Liao, Min ^{[1
,2
]}

Li, Ling ^{[1
,2
]}

Peng, Ying ^{[1
,2
]}

Li, Xuan ^{[1
,2
]}

Pan, Qiong ^{[1
,2
]}

Xie, Qiaoling ^{[1
,2
]}

Li, Qiao ^{[1
,2
]}

Li, Jianwei ^{[8
]}

Li, Ying ^{[9
]}

Chen, Zhe ^{[10
]}

Huang, Yongxiu ^{[10
]}

Assis, David N. ^{[11
,12
]}

Cai, Shi-Ying ^{[11
,12
]}

Boyer, James L. ^{[11
,12
]}

Huang, Xuequan ^{[13
]}

Tang, Can-E ^{[14
,15
]}

Liu, Xiaowei ^{[4
]}

Peng, Shifang ^{[5
]}

Chai, Jin ^{[1
,2
]}

机构：

[1] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Dept Gastroenterol,Inst Digest Dis PLA,Cholestat L, Chongqing 400038, Peoples R China

[2] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Ctr Metab Associated Fatty Liver Dis,Affiliated Ho, Chongqing 400038, Peoples R China

[3] Third Mil Med Univ, Army Med Univ, Daping Hosp, Dept Hematol,Affiliated Hosp 3, Chongqing 400042, Peoples R China

[4] Cent South Univ, Xiangya Hosp, Dept Gastroenterol, Changsha 410008, Peoples R China

[5] Cent South Univ, Xiangya Hosp, Dept Hepatol & Infect Dis, Changsha 410008, Peoples R China

[6] Cent South Univ, Xiangya Hosp, Dept Endocrinol, Changsha 410008, Peoples R China

[7] Wenzhou Med Univ, Affiliated Hosp 1, MAFLD Res Ctr, Dept Hepatol, Wenzhou 325035, Peoples R China

[8] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Hepatobiliary Surg,Affiliated Hosp 1, Chongqing 400038, Peoples R China

[9] Third Mil Med Univ, Army Med Univ, Xinqiao Hosp, Inst Hepatobiliary Surg,Affiliated Hosp 2, Chongqing 400038, Peoples R China

[10] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Dept Hematol,Affiliated Hosp 1, Chongqing 400038, Peoples R China

[11] Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St, New Haven, CT 06520 USA

[12] Yale Univ, Liver Ctr, Sect Digest Dis, Sch Med, 333 Cedar St, New Haven, CT 06520 USA

[13] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Ctr Minimally Invas Intervent,Affiliated Hosp 1, Chongqing 400038, Peoples R China

[14] Cent South Univ, Xiangya Hosp, Inst Med Sci Res, Changsha 410008, Peoples R China

[15] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha 410008, Peoples R China

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

中国国家自然科学基金;

关键词：

GENE-EXPRESSION; CELLS; CIRRHOSIS; RNA;

D O I：

10.1038/s41467-022-34606-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2( +) ACE2 (+) small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC. Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2(+)ACE2(+) small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2(+)ACE2(+) cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27(+) memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2(+)ACE2(+) cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

引用

页数：16

共 37 条

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