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- Title
ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance.
- Authors
Luna Ge; Ting Wang; Dandan Shi; Yun Geng; Huancai Fan; Ruojia Zhang; Yuang Zhang; Jianli Zhao; Shufeng Li; Yi Li; Haojun Shi; Guanhua Song; Jihong Pan; LinWang; Jinxiang Han
- Abstract
Objective: The contribution of activating transcription factor 6a (ATF6a) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6a in RA remains to be fully elucidated. Methods: ATF6a expression was determined in joint tissues and FLS, and gainof- function and loss-of-function analyses were applied to evaluate the biological roles of ATF6a in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6a and treatment with the ATF6a inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6a. Results: ATF6a expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6a silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6a deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6a in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6a. Conclusion: This study highlights the pathogenic role of ATF6a-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.
- Subjects
RHEUMATOID arthritis; APOPTOSIS; COLLAGEN-induced arthritis; EXPERIMENTAL arthritis; CYTOKINES; DELETION mutation
- Publication
Frontiers in Immunology, 2022, Vol 13, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2022.965708