{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:58:09Z","timestamp":1790686689013,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI17\/00785  and  P17\/00993 (JDC)"],"award-info":[{"award-number":["PI17\/00785  and  P17\/00993 (JDC)"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>GM-CSF-dependent macrophage polarization has been demonstrated in rheumatoid arthritis (RA). Our aim was to seek diagnostic\/prognostic biomarkers for undifferentiated arthritis (UA) by analyzing GM-CSF expression and source, macrophage polarization and density in joints of patients with UA evolving to RA or PsA compared with established RA or PsA, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Synovial tissue (ST) from patients with UA evolving to RA (UA&amp;gt;RA, n=8), PsA (UA&amp;gt;PsA, n=9), persistent UA (UA, n=16), established RA (n=12) and PsA (n=10), and healthy controls (n=6), were analyzed. Cell source and quantitative expression of GM-CSF and proteins associated with pro-inflammatory (GM-CSF-driven) and anti-inflammatory (M-CSF-driven) macrophage polarization (activin A, TNF\u03b1, MMP12, and CD209, respectively) were assessed in ST CD163<jats:sup>+<\/jats:sup> macrophages by multicolor immunofluorescence. GM-CSF and activin A levels were also quantified in paired synovial fluid samples. CD163<jats:sup>+<\/jats:sup> macrophage density was determined in all groups by immunofluorescence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Synovial stromal cells (FAP<jats:sup>+<\/jats:sup> CD90<jats:sup>+<\/jats:sup> fibroblast, CD90<jats:sup>+<\/jats:sup> endothelial cells) and CD163<jats:sup>+<\/jats:sup> sublining macrophages were the sources of GM-CSF. ST CD163<jats:sup>+<\/jats:sup> macrophages from all groups expressed pro-inflammatory polarization markers (activin A, TNF\u03b1, and MMP12). Expression of the M-CSF-dependent anti-inflammatory marker CD209 identified two macrophage subsets (CD163<jats:sup>+<\/jats:sup> CD209<jats:sup>high<\/jats:sup> and CD163<jats:sup>+<\/jats:sup> CD209<jats:sup>low\/-<\/jats:sup>). CD209<jats:sup>+<\/jats:sup> macrophages were more abundant in ST from healthy controls and PsA patients, although both macrophage subtypes showed similar levels of pro-inflammatory markers in all groups. In paired synovial fluid samples, activin A was detected in all patients, with higher levels in UA&amp;gt;RA and RA, while GM-CSF was infrequently detected. ST CD163<jats:sup>+<\/jats:sup> macrophage density was comparable between UA&amp;gt;RA and UA&amp;gt;PsA patients, but significantly higher than in persistent UA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>GM-CSF is highly expressed by sublining CD90<jats:sup>+<\/jats:sup> FAP<jats:sup>+<\/jats:sup> synovial fibroblasts, CD90<jats:sup>+<\/jats:sup> activated endothelium and CD163<jats:sup>+<\/jats:sup> macrophages in different types of arthritis. The polarization state of ST macrophages was similar in all UA and established arthritis groups, with a predominance of pro-inflammatory GM-CSF-associated markers. CD163<jats:sup>+<\/jats:sup> macrophage density was significantly higher in the UA phases of RA and PsA compared with persistent UA. Taken together, our findings support the idea that GM-CSF is a strong driver of macrophage polarization and a potential therapeutic target not only in RA but also in PsA and all types of UA.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.613975","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T01:11:22Z","timestamp":1613783482000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":43,"title":["GM-CSF Expression and Macrophage Polarization in Joints of Undifferentiated Arthritis Patients Evolving to Rheumatoid Arthritis or Psoriatic Arthritis"],"prefix":"10.3389","volume":"11","author":[{"given":"Sara","family":"Fuentelsaz-Romero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cuervo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizbeth","family":"Estrada-Capetillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Celis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Garc\u00eda-Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergi","family":"Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Samaniego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amaya","family":"Puig-Kr\u00f6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan 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