Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis

Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis. 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 activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, 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, TNF, IFN-gamma, IL-1 beta or lack thereof, drive four 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.

Automated summary

Smith et al. provide a detailed resource on the factors driving transcriptional heterogeneity of synovial fibroblasts during rheumatoid arthritis. The study explores the communication between immigrant and resident cell types in human inflammatory disease, highlighting the role of local exposure to cytokines in driving distinct fibroblast states. These findings enhance our understanding of the inflamed synovium and its contribution to disease progression.