{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:31:30Z","timestamp":1787725890433,"version":"build-2784847793"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004001","name":"Guizhou Provincial Science and Technology Department","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Rheumatoid arthritis (RA) is characterized by synovial inflammation, synovial fibroblast (SF) activation, and joint destruction. Activated SFs acquire proliferative and invasive properties and interact with macrophages to maintain the inflammatory microenvironment. However, endogenous factors regulating fibroblast activation and fibroblast\u2013macrophage communication in RA are not fully understood. In this study, we examined the expression of insulin-like growth factor binding protein 5 (IGFBP5) in RA synovium at single-cell resolution and investigated its role in SF activation and macrophage polarization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing (scRNA-seq) datasets from normal and RA synovial tissues were reprocessed and integrated using Seurat and Harmony. Sample-level quality-control metrics and cellular composition were evaluated per sample. Donor-level pseudo-bulk analysis and external synovial transcriptomic datasets were used to validate IGFBP5 downregulation. Pseudotime analysis, SAVER imputation, RA-only CellChat analysis, and in silico IGFBP5 perturbation were performed. Disease-associated IGFBP5 expression was evaluated in a collagen-induced arthritis (CIA) mouse model, whereas IGFBP5 overexpression was examined\n                      <jats:italic>in vitro<\/jats:italic>\n                      using RA synovial fibroblasts and a Transwell fibroblast-macrophage coculture system.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq analysis showed that IGFBP5 expression was reduced in RA synovial fibroblasts, particularly in inflammatory and fibrotic subclusters. Donor-level pseudo-bulk analysis supported lower IGFBP5 expression in RA fibroblasts, particularly in lining and sublining fibroblasts, and external datasets showed concordant reductions or downward trends. IGFBP5 expression was negatively associated with pathogenic fibroblast markers FAP and THY1 and positively associated with the homeostatic marker PRG4. In CIA mice, IGFBP5 expression was decreased in hyperplastic synovial tissues and CIA-derived synovial fibroblasts.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , IGFBP5 overexpression reduced fibroblast proliferation, migration, and invasion and increased apoptosis. In Transwell coculture assays, IGFBP5-overexpressing fibroblasts reduced CD86-associated and pro-inflammatory macrophage features and increased the CD86-negative\/CD206-positive macrophage fraction and TGF-\u03b2 and IL-10 secretion, whereas CD206 mean fluorescence intensity was not significantly changed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Reduced IGFBP5 expression is associated with pathogenic fibroblast states in RA. IGFBP5 overexpression\n                      <jats:italic>in vitro<\/jats:italic>\n                      attenuated aggressive features of RA synovial fibroblasts and altered macrophage phenotypic and cytokine profiles in coculture. These findings identify IGFBP5 as a fibroblast-associated pathway involved in synovial fibroblast-macrophage interactions and warrant\n                      <jats:italic>in vivo<\/jats:italic>\n                      intervention studies to establish causality and therapeutic efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1873778","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:03:08Z","timestamp":1787724188000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced fibroblast-derived IGFBP5 is associated with pathogenic synovial fibroblast states and altered macrophage polarization in rheumatoid arthritis"],"prefix":"10.3389","volume":"17","author":[{"given":"Lunmin","family":"Bao","sequence":"first","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Guizhou Medical 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People\u2019s Hospital of Anshun City","place":["Anshun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, People\u2019s Hospital of Anshun City","place":["Anshun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufang","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, School of Clinical Laboratory Science, Guizhou Medical University","place":["Guiyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Immunology, School of Basic Medicine, Guizhou Medical University","place":["Guiyang, Guizhou, China"]},{"name":"Department of Clinical Microbiology and Immunology, School of Clinical Laboratory Science, Guizhou Medical University","place":["Guiyang, 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