Abstract
Immune-mediated inflammatory diseases remain plagued by poor treatment responses and lack curative therapies. Convergent findings suggest a role for the stromal compartment and extracellular matrix composition dysregulation. Using rheumatoid arthritis as a model, we define an analytical pipeline combining transcriptomic, proteomic and degradomic analysis to characterise disease activity-specific matrix perturbations. This revealed synergistic contributions from fibroblasts and myeloid cells to matrix composition, with fibroblast subsets defining distinct subsynovial niches through distinct matrix expression profiles. Transcriptional dysregulation of collagen VI was found to be a feature of RA activity, with collagen VI protein accumulation linked to remission-associated states. Spatial analysis and in vitro migration showed collagen VI inhibits immune ingress, confining infiltrating cells to perivascular pockets termed "COL6 dark" zones. Matrix degradation-associated monocytes were found at the leading edge of these zones, expanding immune-permissive niches, and releasing RA-associated collagen VI fragments. Our work reveals how dynamic matrix remodelling can in turn limit, and enable, cell immigration in RA, identifying a new mechanism controlling tissue-level disease activity.