JAK inhibition prevents the induction of pro-inflammatory HLA-DR+CD90+ RA synovial fibroblasts by IFNɣ

OBJECTIVES Recent transcriptome analyses revealed that 15-fold expanded HLA-DR+ CD90+ synovial fibroblasts (SFs) are potential key mediators of inflammation in rheumatoid arthritis (RA). The reasons for the expansion of HLA-DR+ CD90+ SFs are unclear, but genetic signatures indicated a central role of IFNɣ in the generation of this fibroblast subset. In the present study, we investigated the generation of HLA-DR+ CD90+ SFs and their function. We hypothesized that infiltrating leukocytes such as NK cells become activated in situ, provide IFNɣ and thus contribute to the generation of arthritic HLA-DR+ CD90+ SFs. METHODS We combined functional assays using primary human materials and focused bioinformatic analyses of mass cytometry and transcriptomics patient datasets. RESULTS We detected enriched and activated FcɣRIIIA(CD16)+ NK cells in synovia from active RA. CD16 recognized immune complexes in synovial fluid, potentially contributing to NK cell activation in RA. In vitro, NK cell-derived IFNɣ induced HLA-DR and an inflammatory, cytokine secreting, HLA-DR+ phenotype in CD90+ SFs. HLA-DR+ CD90+ SFs consecutively activated CD4+ T cells upon receptor crosslinking via superantigens. HLA-DR+ CD90+ SFs also activated CD4+ T cells in absence of superantigens, an effect that was boosted by NK cell-derived IFNɣ and that was four times stronger in RA compared to osteoarthritis. Finally, JAK inhibition prevented HLA-DR induction and blocked pro-inflammatory signals to T cells. CONCLUSIONS HLA-DR+ CD90+ SFs are an activation state that can be induced by IFNɣ, likely provided from infiltrating leukocytes such as activated NK cells. The induction of these pro-inflammatory, IL-6 producing and likely antigen-presenting SFs can be targeted by JAK inhibition.