Disease-specific fibroblast-myeloid interactions in rheumatoid arthritis synovium
Rheumatoid arthritis (RA) is characterized by profound remodeling of the synovial microenvironment. Here we show that enhanced fibroblast-macrophage cross-talk distinguishes RA from psoriatic arthritis (PsA). MerTK-SPP1 macrophages represent the dominant inflammatory myeloid population in RA, interacting with expanded fibroblast subsets through SPP1-mediated signaling. Lining fibroblasts display induction of antigen-presentation and IL-6/JAK-STAT pathways, while a CHI3L1-producing fibroblast population arises specifically in RA and may act as a source of autoantigens. These stromal populations interact closely with FABP5 iDC3 cells and T cells within a disrupted synovial lining, creating a niche driving adaptive immune activation. In contrast, PsA exhibits increased fibroblast- endothelial interactions without major endothelial transcriptional changes. Our data identify SPP1 signaling and fibroblast-myeloid-dendritic interactions as core drivers of RA synovial inflammation that links innate immune activation to the initiation of autoimmunity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/688477v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@c76e39org.highwire.dtl.DTLVardef@11563a9org.highwire.dtl.DTLVardef@141f3fborg.highwire.dtl.DTLVardef@f90742_HPS_FORMAT_FIGEXP M_FIG C_FIG