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  3. EZH2 inhibition dampens autoantibody production in lupus by restoring B cell immune tolerance

EZH2 inhibition dampens autoantibody production in lupus by restoring B cell immune tolerance

  • Int Immunopharmacol. 2023 Apr 10;119:110155. doi: 10.1016/j.intimp.2023.110155.
Yiying Yang 1,  Muyuan Li 2,  Yaxi Zhu 3,  Ke Liu 3,  Meidong Liu 3,  Yanjuan Liu 4,  Ganqian Zhu 5,  Hui Luo 6,  Xiaoxia Zuo 6,  Huali Zhang 7,  Muyao Guo 8
Affiliations

Affiliations

  • 1 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China.
  • 2 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China.
  • 3 Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China.
  • 4 Institute of Emergency Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
  • 5 School of Biomedical Sciences, Hunan University, Changsha, Hunan, China.
  • 6 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China.
  • 7 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Pathophysiology, School of Basic Medicine Science, Central South University, Changsha, Hunan, China; Sepsis Translational Medicine Key Lab of Hunan Province, Changsha, Hunan, China. Electronic address: zhanghuali@csu.edu.cn.
  • 8 Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan, China. Electronic address: 4011394@csu.edu.cn.
PMID: 37044035 DOI: 10.1016/j.intimp.2023.110155
Abstract

Objective: The aim of this study was to elucidate the role of enhancer of zeste homolog 2 (EZH2) in the breakdown of B cell immune tolerance and production of autoantibodies in systemic lupus erythematosus (SLE), and to explore the therapeutic effects of EZH2 inhibition on lupus.

Methods: Peripheral blood mononuclear cells (PBMCs) were collected from new-onset SLE patients for flow cytometric analysis. Pristane-induced lupus mice were constructed, and the EZH2 Inhibitor was administrated by intraperitoneal injection to treat lupus mice. Blood and urine were collected from lupus mice to detect autoantibodies and proteinuria, and renal pathology scores were assessed. Mouse spleen B cells were sorted with Magnetic Beads and subjected to flow cytometric Apoptosis detection, real time quantitative PCR (RT-qPCR), and western blotting (WB).

Results: EZH2 expression was elevated in diverse B-cell subsets in both SLE patients and pristane-induced lupus mice. The EZH2 Inhibitor attenuated lupus-like symptoms and dampened autoantibody production in pristane-induced lupus mice. Inhibition of EZH2 also reduced autoantibody secretion by plasma cells from lupus patients. Mechanistically, EZH2 mediated the impaired Apoptosis of autoreactive B cells and the differentiation of autoantibody producing plasma cells by inhibiting multiple cyclin-dependent kinase inhibitor (CKI) genes.

Conclusion: EZH2 mediated the breakdown of B-cell peripheral immune tolerance by inhibiting CKI genes and participated in the generation of autoantibodies in SLE. EZH2 inhibition could serve as a promising drug intervention for the treatment of SLE.

Keywords

Apoptosis; Autoantibody; B cell; EZH2; Immune tolerance; SLE.

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