Heterogeneity of Inflammation-associated Synovial Fibroblasts in Rheumatoid Arthritis and Its Drivers

Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand the spectrum of states observed in cells that are constitutively resident. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored heterogeneity of synovial fibroblasts (FLS) in inflamed joints of rheumatoid arthritis (RA) patients using paired single cell RNA and ATAC sequencing (scRNA/ATAC-seq), multiplexed imaging, and spatial transcriptomics along with in vitro modeling of cell extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell derived cytokines, TNFα, IFNγ, IL-1β, or lack thereof, drive six distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium. ### Competing Interest Statement AYR is an SAB member, has equity in Sonoma Biotherapeutics and Vedanta Biosciences, and is a co-inventor or has IP licensed to Takeda that is unrelated to the content of the present study. The remaining authors declare no competing interests.