PPAR-γ alleviates the inflammatory response in TNF-α-induced fibroblast-like synoviocytes by binding to p53 in rheumatoid arthritis

Xiao-feng Li1,2, Shu-qin Yin1,2,3, Hao Li1,2, Ying-li Yang1,2, Xin Chen1,2, Biao Song4, Sha Wu1,2, Yuan-yuan Wu1,2, Hua Wang5, Jun Li1,2
1 Inflammation and Immune Mediated Disease Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China
2 The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei 230032, China
3 Pharmacy Department, Chizhou People’s Hospital, Chizhou 247000, China
4 Pharmacy Department, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
5 Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
Correspondence to: Hua Wang:, Jun Li:,
DOI: 10.1038/s41401-022-00957-9
Received: 24 March 2022
Accepted: 10 July 2022
Advance online: 2 August 2022


Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-γ inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-γ in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg·kg−1·d−1) or rosiglitazone (4 mg·kg−1·d−1) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-γ+/− mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/−) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/− CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.

Keywords: rheumatoid arthritis; fibroblast-like synoviocytes; inflammatory response; PPAR-γ; adjuvant-induced arthritis collagen-induced arthritis

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