TNFR2 is critical for TNF-induced rheumatoid arthritis fibroblast-like synoviocyte inflammation. (8th March 2022)

• Record Type: Journal Article
• Authors: Suto, Takahito; Tosevska, Anela; Dalwigk, Karolina; Kugler, Maximillian; Dellinger, Mirjam; Stanic, Irena; Platzer, Alexander; Niederreiter, Birgit; Sevelda, Florian; Bonelli, Michael; Pap, Thomas; Kiener, Hans; Okamura, Koichi; Chikuda, Hirotaka; Aletaha, Daniel; Heinz, Leonhard X; Karonitsch, Thomas
• Is Part Of: Rheumatology. Volume 61:Number 11(2022)
• Page Start: 4535
• Page End: 4546
• Publication Date: 2022-03-08
• Subjects: RA -- fibroblast-like synoviocytes (FLS) -- TNF -- TNF-receptor (TNFR) -- STAT1 -- synovitis; Rheumatism -- Periodicals; Rheumatology -- Periodicals; 616.723005
• DOI: 10.1093/rheumatology/keac124
• Languages: English
• ISSNs: 1462-0324

Abstract

Abstract: Objectives: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in RA. The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. Methods: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. Results: TNFR2 expression was increased in RA when compared with OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared with OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1β were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. Conclusion: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.