Kdm5a promotes B cell activation in systemic lupus erythematosus via downregulation of A20 by histone modification

Jie Fan; S Iwata; Yoshiya Tanaka; Yukihiro Kitanaga; Akina Ishii; Hara Maiko; Xueqiang Zhang; Xingde Liu

doi:10.1016/j.prp.2021.153653

Kdm5a promotes B cell activation in systemic lupus erythematosus via downregulation of A20 by histone modification

Pathol Res Pract. 2021 Oct 9:153653. doi: 10.1016/j.prp.2021.153653. Online ahead of print.

Authors

Jie Fan¹, S Iwata², Yoshiya Tanaka³, Yukihiro Kitanaga², Akina Ishii², Hara Maiko², Xueqiang Zhang¹, Xingde Liu⁴

Affiliations

¹ Department of Cardiology, Handan Central Hospital, China.
² First Department of Internal Medicine, Dean Graduate School of Medical Science University of Occupational and Environmental, Japan.
³ First Department of Internal Medicine, Dean Graduate School of Medical Science University of Occupational and Environmental, Japan. Electronic address: y.tanaka.ryu@gmail.com.
⁴ Department of Cardiology, Guizhou University of Traditional Chinese Medicine, China.

PMID: 34763954
DOI: 10.1016/j.prp.2021.153653

Abstract

Systemic lupus erythematosus (SLE) is a classic autoimmune connective tissue disease, which leads to multiple organ system injury. Tumor necrosis factor-induced protein 3 (TNFAIP3), generally called A20, has been documented to go together with the development of SLE. However, the role and mechanism of A20 in the progression of SLE are still unrevealed. In our study, A20 was downregulated in B cells from SLE patients and B cell responsiveness was significantly elevated in SLE patients. Overexpression of A20 restrained the proliferation and induced the apoptosis of B cells. Additionally, trimethylation of histone H3 Lysine 4 (H3K4me3) was decreased in the A20 promoter of SLE B cells. Lysine demethylase 5 A (Kdm5a) was significantly increased in B cells from SLE patients and negatively correlated with A20 expression. Further, Kdm5a knockdown increased the H3K4me3 level and A20 expression. More importantly, Kdm5a promoted the proliferation and inhibited the apoptosis of B cells in SLE via downregulation of A20. In general, Kdm5a promoted the proliferation and inhibited the apoptosis of B cells in SLE via downregulation of A20 by decreasing H3K4me3 enrichment level in the A20 promoter, suggesting a novel mechanism underlying SLE progression, and providing a promising therapeutic target for SLE. AVAILABILITY OF DATA AND MATERIALS: All data generated or analyzed during this study are included in this published article and its additional files.

Keywords: B cells; Lysine demethylase 5A; Systemic lupus erythematosus; Tumor necrosis factor-induced protein 3.