Disease-specific fibroblast-myeloid interactions in rheumatoid arthritis synovium

Khmelevskaya, A.; Apostolopoulou, K.; Calvo Cebrian, C.; Ezen, E.; Toitou, M.; Laphanuwat, P.; Mirrsahimi, M.; Geiss, C.; Lugar, M.; Kakale, A.; Malkewitz, S.; Laimbacher, A.; Konstantopoulos, D.; Rinotas, V.; Armaka, M.; Houtman, M.; Meier, E.; Bürki, K.; Leclerc, J.; Mohammadian, H.; Seiler, C.; Camarillo-Retamosa, E.; Pauli, C.; Ramming, A.; Fearon, U.; Zachariassen, K.; Rauer, T.; Ciurea, A.; Elhai, M.; Micheroli, R.; Ospelt, C.

doi:10.1101/2025.11.17.688477

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bioRxiv · 10.1101/2025.11.17.688477

Disease-specific fibroblast-myeloid interactions in rheumatoid arthritis synovium

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Abstract

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

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Khmelevskaya, A., Apostolopoulou, K., Calvo Cebrian, C., Ezen, E., Toitou, M., Laphanuwat, P., Mirrsahimi, M., Geiss, C., Lugar, M., Kakale, A., Malkewitz, S., Laimbacher, A., Konstantopoulos, D., Rinotas, V., Armaka, M., Houtman, M., Meier, E., Bürki, K., Leclerc, J., Mohammadian, H., Seiler, C., Camarillo-Retamosa, E., Pauli, C., Ramming, A., Fearon, U., Zachariassen, K., Rauer, T., Ciurea, A., Elhai, M., Micheroli, R., Ospelt, C.. 2025-11-17. Disease-specific fibroblast-myeloid interactions in rheumatoid arthritis synovium. https://doi.org/10.1101/2025.11.17.688477

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