SPP1 hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

Abstract In chronic inflammatory diseases, maladaptive tissue remodelling is driven by a complex interplay of resident cells, immune filtrates and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes assive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this ggressive growth are incompletely defined. Using spatial transcriptomics profiling of patient tissue, we detected an bundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to SPP1hi macrophages. Notably, ese synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. While the SPP1hi acrophages phenotypically resemble pro-fibrotic macrophages that drive lung and liver fibrosis, these niches were devoid f the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1hi macrophages degrade and hagocytose fibrin matrices and promote fibroblast proliferation. As fibrin provides transient matrices for de novo tissue eneration in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1hi acrophages, fibroblasts and fibrin matrices adhered to the exterior synovial tissue surface. While current RA therapies rimarily aim to dampen pro-inflammatory responses, our findings provide rationale for targeting pro-generative pathways nd SPP1hi macrophages. Once Sentence Summary SPP1hi macrophages in RA synovial fibrin deposits promote tissue hyperplasia. Competing Interest Statement A.Y.R. is a paid Scientific Advisory Board (SAB) member of and holds equity in Sonoma Biotherapeutics, Odyssey Therapeutics, and Nilo Therapeutics; he is also an SAB member of Amgen. K. Wei was a consultant for Mestag Therapeutics and Gilead Sciences and reported grant support from Gilead Sciences. I.M. and L.T.D. are co-inventors on a pending patent application related to the findings described in this manuscript. All other authors declare that they have no competing interests.