Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis
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Published:2024-02-01
Issue:
Volume:
Page:ard-2023-224878
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ISSN:0003-4967
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Container-title:Annals of the Rheumatic Diseases
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language:en
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Short-container-title:Ann Rheum Dis
Author:
Hu FanleiORCID, Shi LianjieORCID, Liu Xiaohang, Chen Yingjia, Zhang XiaORCID, Jia Yuan, Liu Xu, Guo Jianping, Zhu HuaqunORCID, Liu Hongjiang, Xu LilingORCID, Li Yingni, Wang Ping, Fang Xiangyu, Xue Jimeng, Xie Yang, Wei ChaonanORCID, Song Jing, Zheng Xi, Liu Yan-Ying, Li Yuhui, Ren Limin, Xu Dakang, Lu Liwei, Qiu Xiaoyan, Mu Rong, He JingORCID, Wang Min, Zhang XuanORCID, Liu Wanli, Li ZhanguoORCID
Abstract
ObjectivesB10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases.MethodsThe frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α−/−and B cell-specific SHIP-1−/−mouse disease model studies.ResultsTNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α−/−mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells.ConclusionsTNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.
Funder
Peking University People’s Hospital Basic and Applied Basic Research Foundation of Guangdong Province Macau Science and Technology Development Fundation Beijing Nova Program Beijing Municipal Natural Science Foundation National Natural Science Foundation of China National Science and Technology Major Project Peking University
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology
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