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Extracellular Inosine Induces Anergy in B Cells to Alleviate Autoimmune Hepatitis

文献类型：期刊论文

作者Cui, Nana3; Qian, Qiwei3; Zhou, Yujie3; Zhang, Heng2; Zhang, Huayang3; Wang, Binghong3; Li, Yikang3; Wang, Qixia3; Lian, Min3; You, Zhengrui3
刊名CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
出版日期2025
卷号19期号:10页码:17
关键词Anergic B Cells Autoimmune Hepatitis CD73 Equilibrative Nucleoside Transporter 1 Inosine
ISSN号2352-345X
DOI10.1016/].]cmgh.2025.101539
英文摘要BACKGROUND & AIMS: Dysregulation of na & iuml;ve B cell receptor (BCR) signaling and the generation of antibody-secreting B cells (ASCs) have been implicated in the development of autoimmune diseases. Anergic B cells (BNDs) are na & iuml;ve B cells with a low-density of surface IgM-BCR, thus demonstrating attenuated autoantigen responsiveness. However, potential regulatory mechanisms of B cell anergy and their roles in autoimmune hepatitis (AIH) remain unestablished. METHODS: The frequency of circulating B cell subsets and comparative phenotypic analyses were conducted using flow cytometry. Primary human CD19 & thorn; B cells were differentiated in vitro with inosine or specific inhibitors, followed by quantitative polymerase chain reaction (qPCR), Western blotting, and flow cytometry analyses. The effects of inosine were evaluated in a concanavalin A-induced AIH mouse model, and a specific equilibrative nucleoside transporter 1 (ENT1) inhibitor was utilized both in vitro and in vivo. RESULTS: An elevated frequency of ASCs but a diminish of BNDs were observed in AIH. BNDs showed attenuated activated status compared with CNBs. BNDs uniquely exhibited high-level expression of CD73, the rate-limiting enzyme in purinergic metabolism. Inosine, as the end-product of the extracellular purinergic pathway, significantly enhanced BNDs expansion and inhibited ASCs differentiation in vitro. Mechanically, extracellular inosine was taken up via ENT1, promoting surface IgM internalization by inhibiting the PARP14-STAT6 signaling pathway. Pharmacological inhibition of ENT1 with dipyridamole reversed therapeutic effects of inosine both in vitro and in vivo. CONCLUSIONS: Our findings revealed that inosine was a crucial metabolite that induced immune tolerance of B cells, thus proposing a potential intervention strategy for AIH. (Cell Mol Gastroenterol Hepatol 2025;19:101539; https://doi.org/ 10.1016/].]cmgh.2025.101539)
WOS关键词T-CELL ; ADENOSINE ; EXPRESSION
资助项目National Natural Science Foundation of China[82130017] ; National Natural Science Foundation of China[82330018] ; National Natural Science Foundation of China[82270553] ; National Natural Science Foundation of China[82270663] ; Innovative Research Team of High-level Local Universities in Shanghai[SHSMU-ZDCX20210301] ; Innovative Research Team of High-level Local Universities in Shanghai[SHSMU-ZDCX20211600] ; Shanghai Rising-Star Program[22QA1405500] ; Shanghai Science and Technology Commission[21JC1404200] ; Shanghai Top-Priority Medical Center Construction Project[2023ZZ02022]
WOS研究方向Gastroenterology & Hepatology
语种英语
WOS记录号WOS:001581050500001
出版者ELSEVIER INC
源URL[http://119.78.100.183/handle/2S10ELR8/321573]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Lian, Min; You, Zhengrui; Ma, Xiong
作者单位1.Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Inst Aging & Tissue Regenerat, Shanghai, Peoples R China
2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
3.Shanghai Jiao Tong Univ, Renji Hosp,NHC Key Lab Digest Dis, Shanghai Inst Digest Dis,Minist Hlth,State Key Lab, Sch Med,Div Gastroenterol & Hepatol,Key Lab Gastro, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Cui, Nana,Qian, Qiwei,Zhou, Yujie,et al. Extracellular Inosine Induces Anergy in B Cells to Alleviate Autoimmune Hepatitis[J]. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,2025,19(10):17.
APA Cui, Nana.,Qian, Qiwei.,Zhou, Yujie.,Zhang, Heng.,Zhang, Huayang.,...&Ma, Xiong.(2025).Extracellular Inosine Induces Anergy in B Cells to Alleviate Autoimmune Hepatitis.CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,19(10),17.
MLA Cui, Nana,et al."Extracellular Inosine Induces Anergy in B Cells to Alleviate Autoimmune Hepatitis".CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY 19.10(2025):17.

入库方式： OAI收割

来源：上海药物研究所

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