<i>SPP1</i> <sup>hi</sup> macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium
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.
Authors
- J. Rangel-Moreno
- Michael Brenner
- Kamil Slowikowski (ORCID: https://orcid.org/0000-0002-2843-6370)
- Kevin D. Deane (ORCID: https://orcid.org/0000-0003-2211-4861)
- William Apruzzese (ORCID: https://orcid.org/0000-0003-4037-6160)
- Laura T. Donlin (ORCID: https://orcid.org/0000-0002-1428-090X)
- David Boyle (ORCID: https://orcid.org/0000-0003-3352-5092)
- Ummara Shah
- Alexander Y. Rudensky (ORCID: https://orcid.org/0000-0003-1280-2898)
- Susan M. Goodman (ORCID: https://orcid.org/0000-0003-1197-7864)
- Joel M. Guthridge (ORCID: https://orcid.org/0000-0002-9308-237X)
- Kushal K. Dey (ORCID: https://orcid.org/0000-0002-3520-2345)
- Dana E. Orange (ORCID: https://orcid.org/0000-0001-9859-7199)
- V. Michael Holers (ORCID: https://orcid.org/0000-0002-5634-7746)
- Melanie H. Smith (ORCID: https://orcid.org/0000-0003-2464-8429)
- Andrew D. Filer (ORCID: https://orcid.org/0000-0001-8164-6249)
- Ilya Korsunsky (ORCID: https://orcid.org/0000-0003-4848-3948)
- Kevin Wei (ORCID: https://orcid.org/0000-0002-1821-167X)
- Miriam R. Fein (ORCID: https://orcid.org/0000-0003-3403-8798)
- Daniel C. Ramirez (ORCID: https://orcid.org/0000-0003-1388-7002)
- María Gutiérrez‐Arcelus (ORCID: https://orcid.org/0000-0001-7898-7691)
- Nirmal K. Banda (ORCID: https://orcid.org/0000-0002-5291-5136)
- J. Hossler
- Costantino Pitzalis (ORCID: https://orcid.org/0000-0003-1326-5051)
- Hope A. Townsend (ORCID: https://orcid.org/0009-0001-5998-3369)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-6102-2970)
- Larry W. Moreland (ORCID: https://orcid.org/0000-0003-4483-0359)
- Mina Rohani‐Pichavant
- Nida Meednu (ORCID: https://orcid.org/0000-0002-2868-3339)
- Richard D. Bell (ORCID: https://orcid.org/0000-0003-1562-3879)
- Edward F. DiCarlo (ORCID: https://orcid.org/0000-0001-5775-3167)
- Soumya Raychaudhuri (ORCID: https://orcid.org/0000-0002-1901-8265)
- Amit Lakhanpal (ORCID: https://orcid.org/0000-0003-4171-4790)
- Thomas M. Norman (ORCID: https://orcid.org/0000-0002-3755-4379)
- Christina S. Leslie (ORCID: https://orcid.org/0000-0002-4571-5910)
- Robert Ike
- Judith A. James (ORCID: https://orcid.org/0000-0002-9574-7355)
- Jennifer Seifert (ORCID: https://orcid.org/0000-0001-5851-7246)
- Ian Mantel (ORCID: https://orcid.org/0000-0003-2609-4028)
- Ce Gao (ORCID: https://orcid.org/0000-0001-9804-261X)
- Laura B. Hughes
- Gary S. Firestein
- Diane Horowitz
- D. H. Parks
- Holden Maecker (ORCID: https://orcid.org/0000-0001-5389-0906)
- PJ Utz
- Maria Sargent
- Louis Bridges
- B.F. Boyce
- Yvonne Lee
- Joan Bathon
- Eric Matteson
- Jennifer Anolik
- Holly Adams
- Accelerating Medicines Partnership: RA/SLE Network
- Haoxuan Zhang
- Juan Vargas
- Harris Perlman
- Christopher Ritchlin
- Joshua Keegan
- Lindsy Forbess
- Endo Yoshimi
- Karen Salomon-Escoto
- Vivian Bykerk
- Yanyan Liu
- Gerald Watts
- David Fox
- Jason Turner
- Peter Gregersen
- Stephen Kelly
- Ellen Gravallese
- Jim Lederer
- Darren Tabechian
- Aaron Wise
- Kazuyoshi Ishigaki
- Deepak Rao
- Rebecca Hands
- Veronica Gonzales
- Emily Bacalao
- William Robinson
- Ami Ben-Artzi
- Lionel Ivashkiv
- Rohit Gupta
- Thomas Eisenhaure
- John Atkinson
- Andrew Cordle
- David Lieb
- Michael H. Weisman
- R. Thiele
- Adam Chicoine
- Chamith Fonseka
- Mandy J. McGeachy
- Arnon Arazi
- Arthur Mandelin
- O. Nwawka
- Nir Hacohen
Institutions
- Hospital for Special Surgery (US)
- Brigham and Women's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Colorado School of Public Health (US)
- University of Colorado Boulder (US)
- Cornell University (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Weill Cornell Medicine (US)
- University of Colorado Anschutz Medical Campus (US)
- Rockefeller University (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2026-06-24
- DOI
- https://doi.org/10.1126/scitranslmed.aed3087
- Primary Topic
- Rheumatoid Arthritis Research and Therapies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Burroughs Wellcome Fund
- Wellcome Trust
- Shurl and Kay Curci Foundation
- National Human Genome Research Institute
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Arthritis and Musculoskeletal and Skin Diseases