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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.

Titel:	Mutant p53 <superscript>R211*</superscript> ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.
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
Link:	Full Text Finder (Volltext)
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
Schlagwort:	Animals Humans Rats Cytokines metabolism Immunity, Innate Interferon Regulatory Factor-3 Protein Serine-Threonine Kinases Tumor Suppressor Protein p53 genetics Arthritis, Experimental drug therapy Arthritis, Experimental genetics Arthritis, Rheumatoid drug therapy Arthritis, Rheumatoid genetics
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Inflamm Res] 2023 Dec; Vol. 72 (12), pp. 2199-2219. <i>Date of Electronic Publication: </i>2023 Nov 08. MeSH Terms: Arthritis, Experimental* / drug therapy ; Arthritis, Experimental* / genetics ; Arthritis, Rheumatoid* / drug therapy ; Arthritis, Rheumatoid* / genetics ; Animals ; Humans ; Rats ; Cytokines / metabolism ; Immunity, Innate ; Interferon Regulatory Factor-3 ; Protein Serine-Threonine Kinases ; Tumor Suppressor Protein p53 / genetics References: Arthritis Res. 2001;3(1):13-7. (PMID: 11178123) ; Cell. 2004 Dec 17;119(6):847-60. (PMID: 15607980) ; Cell. 1993 Nov 19;75(4):817-25. (PMID: 8242752) ; J Immunother Cancer. 2015 Mar 24;3:9. (PMID: 25806108) ; Sci Rep. 2016 Oct 06;6:34617. (PMID: 27708408) ; Immunol Rev. 2010 Jan;233(1):233-55. (PMID: 20193003) ; Immunol Lett. 2009 May 14;124(1):9-17. (PMID: 19446344) ; Mod Rheumatol. 2007;17(4):290-5. 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(PMID: 16970679) Grant Information: 0003/2019/AKP Macao Science and Technology Development Fund; 2019WGALH01 the Joint Fund of Wuyi University-Macau Contributed Indexing: Keywords: IRF3; Rheumatoid arthritis; STING; TBK1; p53 mutant Substance Nomenclature: 0 (Cytokines) ; 0 (Interferon Regulatory Factor-3) ; 0 (IRF3 protein, human) ; EC 2.7.11.1 (Protein Serine-Threonine Kinases) ; EC 2.7.11.1 (TBK1 protein, human) ; 0 (Tumor Suppressor Protein p53) ; EC 2.7.11.1 (Tbk1 protein, rat) ; 0 (Tp53 protein, rat) Entry Date(s): Date Created: 20231107 Date Completed: 20231121 Latest Revision: 20231121 Update Code: 20240514 PubMed Central ID: PMC10656327

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Mutant p53 <superscript>R211*</superscript> ameliorates inflammatory arthritis in AIA rats via inhibition of TBK1-IRF3 innate immune response.