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Therefore, the aim of this study was to determine the expression and function of Sema4B in RA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Peripheral blood monocytes from healthy controls (HC) and patients with RA were differentiated into M1 macrophages and stimulated with Sema4B and LPS alone and in combination. Fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and RA and 3D synovium micromasses, formed by RA FLS and RA monocytes, were stimulated with Sema4B and TNF-\u03b1 alone and in combination. PlexinB2 expression was knocked down using siRNA. <jats:italic>Synovial<\/jats:italic> mRNA expression was obtained from gene expression array in GEO-NCBI and determined by (q)uantitative PCR. Protein expression was determined by immunohistochemistry, immunoblotting and ELISA. FLS viability, <jats:italic>invasion<\/jats:italic> and migration were determined using calcein, <jats:italic>invasion and<\/jats:italic> wound repair scratch assays, respectively.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>The expression of Sema4B was higher in the synovial tissue of patients with RA, as well as in RA FLS compared to OA FLS. Importantly, the stimulation of RA FLS and RA M\u00d8 with inflammatory mediators induced the expression of Sema4B. Functionally, Sema4B alone induced FLS migration <jats:italic>and invasion<\/jats:italic>, and enhanced the TNF-\u03b1 or LPS-induced production of inflammatory mediators (Interleukin (IL)-6, IL-8, TNF-\u03b1, CCL-2) and matrix metalloproteases (MMP-1 and MMP-3) in RA FLS, RA M\u00d8 and the 3D synovium model. In RA FLS, this effect was mediated by the receptor PlexinB2.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In an inflammatory context, Sema4B induces <jats:italic>an aggressive<\/jats:italic> FLS <jats:italic>phenotype<\/jats:italic> and the production of pro-inflammatory mediators by FLS and M\u00d8. These results suggest that Sema4B is involved in the <jats:italic>pathogenic<\/jats:italic> processes observed within the RA synovium.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13075-025-03592-x","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T13:17:51Z","timestamp":1751375871000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Semaphorin4B is elevated in rheumatoid arthritis and enhances the inflammatory phenotype of macrophages and fibroblast-like synoviocytes"],"prefix":"10.1186","volume":"27","author":[{"given":"Sara","family":"Mart\u00ednez-Ramos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Rafael-Vidal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Marty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Malvar-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coral","family":"Mouri\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nair","family":"P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Altab\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J. 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