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

Authors

Ian Mantel, Haoxuan Zhang, Juan Vargas, Gao Ce, Hope Townsend, Richard Bell, Amit Lakhanpal, Miriam R Fein, Accelerating Medicines Partnership: RA/SLE Network, Thomas M Norman, Dana E Orange, Daniel C Ramirez, Edward F DiCarlo, Susan M Goodman, Melanie H Smith, Fan Zhang, Kevin Wei, Kushal K Dey, Alexander Y Rudensky, Christina S Leslie, Laura T Donlin

Published in

Science translational medicine. Volume 18. Issue 855. Pages eaed3087. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

In chronic inflammatory diseases, maladaptive tissue remodeling is driven by a complex interplay of resident cells, immune infiltrates, and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes massive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this aggressive growth are incompletely defined. Using spatial transcriptomic profiling of patient tissue, we detected an abundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to macrophages expressing high levels of secreted phosophoprotein-1 (encoding osteopontin; SPP1^hi macrophages). These synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. Although the SPP1^hi macrophages phenotypically resembled the profibrotic macrophages that drive lung and liver fibrosis, these niches were devoid of the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1^hi macrophages degraded and phagocytosed fibrin matrices and promoted fibroblast proliferation. Given that fibrin provides transient matrices for de novo tissue generation in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1^hi macrophages, fibroblasts, and fibrin matrices adhered to the exterior synovial tissue surface. Whereas current RA therapies primarily aim to dampen proinflammatory responses, our findings provide the rationale for targeting progenerative pathways and SPP1^hi macrophages.

PMID:
42341080
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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