Mutant p53R211* ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response

被引：5

作者：

Zeng, Yaling ^{[1
]}

Ng, Jerome P. L. ^{[1
]}

Wang, Linna ^{[1
]}

Xu, Xiongfei ^{[1
]}

Law, Betty Yuen Kwan ^{[1
]}

Chen, Guobing ^{[2
]}

Lo, Hang Hong ^{[1
]}

Yang, Lijun ^{[1
]}

Yang, Jiujie ^{[1
]}

Zhang, Lei ^{[1
]}

Qu, Liqun ^{[1
]}

Yun, Xiaoyun ^{[1
]}

Zhong, Jing ^{[1
]}

Chen, Ruihong ^{[1
]}

Zhang, Dingqi ^{[1
]}

Wang, Yuping ^{[1
]}

Luo, Weidan ^{[1
]}

Qiu, Congling ^{[2
]}

Huang, Baixiong ^{[1
]}

Liu, Wenfeng ^{[3
]}

Liu, Liang ^{[1
]}

Wong, Vincent Kam Wai ^{[1
]}

机构：

[1] Macau Univ Sci & Technol, Dr Nehers Biophys Lab Innovat Drug Discovery, State Key Lab Qual Res Chinese Med, Taipa 999078, Peoples R China

[2] Jinan Univ, Inst Geriatr Immunol, Sch Med, Dept Microbiol & Immunol, Guangzhou 510630, Peoples R China

[3] Wuyi Univ, Sch Biotechnol & Hlth Sci, Jiangmen 529020, Peoples R China

来源：

INFLAMMATION RESEARCH | 2023年 / 72卷 / 12期

关键词：

p53; mutant; Rheumatoid arthritis; TBK1; IRF3; STING; FIBROBLAST-LIKE SYNOVIOCYTES; RHEUMATOID-ARTHRITIS; SYNOVIAL FIBROBLAST; DRUG-RESISTANCE; IN-VITRO; P53; GAIN; EXPRESSION; GENE; MUTATIONS; CANCER;

D O I：

10.1007/s00011-023-01809-w

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Background: Rheumatoid arthritis (RA) is an autoimmune inflammation disease characterized by imbalance of immune homeostasis. p53 mutants are commonly described as the guardian of cancer cells by conferring them drug-resistance and immune evasion. Importantly, p53 mutations have also been identified in RA patients, and this prompts the investigation of its role in RA pathogenesis.Methods: The cytotoxicity of disease-modifying anti-rheumatic drugs (DMARDs) against p53 (wild-type (WT)/mutant)-transfected RA fibroblast-like synoviocytes (RAFLSs) was evaluated by MTT assay. Adeno-associated virus (AAV) was employed to establish p53 (WT/R211*) adjuvant-induced arthritis (AIA) rat model. The arthritic condition of rats was assessed by various parameters such as micro-CT analysis. Knee joint samples were isolated for total RNA sequencing analysis. The expressions of cytokines and immune-related genes were examined by qPCR, ELISA assay and immunofluorescence. The mechanistic pathway was determined by immunoprecipitation and Western blotting in vitro and in vivo.Results: Among p53 mutants, p53(R213*) exhibited remarkable DMARD-resistance in RAFLSs. However, AAV-induced p53(R211*) overexpression ameliorated inflammatory arthritis in AIA rats without Methotrexate (MTX)-resistance, and our results discovered the immunomodulatory effect of p53(R211*) via suppression of T-cell activation and T helper 17 cell (Th17) infiltration in rat joint, and finally downregulated expressions of pro-inflammatory cytokines. Total RNA sequencing analysis identified the correlation of p53(R211*) with immune-related pathways. Further mechanistic studies revealed that p53(R213*/R211*) instead of wild-type p53 interacted with TANK-binding kinase 1 (TBK1) and suppressed the innate immune TBK1-Interferon regulatory factor 3 (IRF3)-Stimulator of interferon genes (STING) cascade.Conclusions: This study unravels the role of p53(R213*) mutant in RA pathogenesis, and identifies TBK1 as a potential anti-inflammatory target.

引用

页码：2199 / 2219

页数：21

共 90 条

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