IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes: JAKinibs suppress the interferon response in RA-FLSs

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs. IRF-1: a key regulator in rheumatoid Arthritis Thomas Karonitsch at the Medical University of Vienna, Austria, and colleagues showed that activation of the protein interferon regulatory factor 1 (IRF-1) in human synoviocytes promoted the expression of genes that contribute to sustained synovial inflammation in rheumatoid Arthritis (RA). They found that the Januse kinase (JAK) inhibitors baricitinb and tofacitinib, which are both approved for the treatment of RA, prevented the activation of IRF1 regulated proinflammatory genes. Their findings unvover a potential role for IRF1 activated genes as a biomarker to predict the treatment response to RA therapies and moreover highlight the benefit of targeting inflammatory pathways in synoviocytes for the treatment of RA.