Mutant p53 <superscript>R211*</superscript> ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.
In: Inflammation research : official journal of the European Histamine Research Society ... [et al.], Jg. 72 (2023-12-01), Heft 12, S. 2199-2219
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Zugriff:
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.
(© 2023. The Author(s).)
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Mutant p53 <superscript>R211*</superscript> ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.
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Autor/in / Beteiligte Person: | Zeng, Y ; Ng, JPL ; Wang, L ; Xu, X ; Law, BYK ; Chen, G ; Lo, HH ; Yang, L ; Yang, J ; Zhang, L ; Qu, L ; Yun, X ; Zhong, J ; Chen, R ; Zhang, D ; Wang, Y ; Luo, W ; Qiu, C ; Huang, B ; Liu, W ; Liu, L ; Wong, VKW |
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Zeitschrift: | Inflammation research : official journal of the European Histamine Research Society ... [et al.], Jg. 72 (2023-12-01), Heft 12, S. 2199-2219 |
Veröffentlichung: | Basel, Switzerland : Birkhäuser, c1995-, 2023 |
Medientyp: | academicJournal |
ISSN: | 1420-908X (electronic) |
DOI: | 10.1007/s00011-023-01809-w |
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