Biology subjects

Rinotas, V.

Publications and source records attributed to Rinotas, V..

2 recordsLinked to original sources

bioRxiv2025

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

immunology↗

bioRxiv2023

Cyld aborts hyperactivation of synovial fibroblasts in inflammatory arthritis by regulating the TAK1/IKK2 signaling axis

TNF is a potent cytokine known for its involvement in physiology and pathology. In Rheumatoid Arthritis (RA), persistent TNF signals cause aberrant activation of synovial fibroblasts (SFs), the resident cells crucially involved in the inflammatory and destructive responses of the affected synovial membrane. However, the molecular switches that control the pathogenic activation of SFs remain poorly defined. Cyld is a major component of deubiquitination (DUB) machinery regulating the signaling responses towards survival/inflammation and programmed necrosis that induced by cytokines, growth factors and microbial products. Here we follow functional genetic approaches to understand how Cyld affects arthritogenic TNF signaling in SFs. We demonstrate that in spontaneous and induced RA models, SF-Cyld DUB deficiency deteriorates arthritic phenotypes due to increased levels of chemokines, adhesion receptors and bone-degrading enzymes generated by mutant SFs. Mechanistically, Cyld serves to restrict the TNF-induced hyperactivation of SFs by limiting Tak1-mediated signaling, and, therefore, leading to supervised NFkB and JNK activity. However, Cyld is not critically involved in the regulation of TNF-induced death of SFs. Our results identify SF-Cyld as a regulator of TNF-mediated arthritis and inform the signaling landscape underpinning the SF responses.

immunology↗