{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:48:51Z","timestamp":1787849331903,"version":"build-2784847793"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by vasculopathy and progressive fibrosis of skin and several internal organs, including lungs. Macrophages are the main cells involved in the immune-inflammatory damage of skin and lungs, and alternatively activated (M2) macrophages seem to have a profibrotic role through the release of profibrotic cytokines (IL10) and growth factors (TGF\u03b21). Nintedanib is a tyrosine kinase inhibitor targeting several fibrotic mediators and it is approved for the treatment of SSc-related interstitial lung disease (ILD). The study aimed to evaluate the effect of nintedanib in downregulating the profibrotic M2 phenotype in cultured monocyte-derived macrophages (MDMs) obtained from SSc-ILD patients.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Fourteen SSc patients, fulfilling the 2013 ACR\/EULAR criteria for SSc, 10 SSc patients affected by ILD (SSc-ILD pts), 4 SSc patients non affected by ILD (SSc pts no-ILD), and 5 voluntary healthy subjects (HSs), were recruited at the Division of Clinical Rheumatology-University of Genova, after obtaining Ethical Committee approval and patients\u2019 informed consent. Monocytes were isolated from peripheral blood, differentiated into MDMs, and then maintained in growth medium without any treatment (untreated cells), or treated with nintedanib (0.1 and 1\u00b5M) for 3, 16, and 24\u00a0h. Gene expression of macrophage scavenger receptors (CD204, CD163), mannose receptor-1 (CD206), Mer tyrosine kinase (MerTK), identifying M2 macrophages, together with TGF\u03b21 and IL10, were evaluated by quantitative real-time polymerase chain reaction. Protein synthesis was investigated by Western blotting and the level of active TGF\u03b21 was evaluated by ELISA. Statistical analysis was carried out using non-parametric Wilcoxon test.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Cultured untreated SSc-ILD MDMs showed a significant increased protein synthesis of CD206 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), CD204, and MerTK (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01), together with a significant upregulation of the gene expression of MerTK and TGF\u03b21 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) compared to HS-MDMs. Moreover, the protein synthesis of CD206 and MerTK and the gene expression of TGF\u03b21 were significantly higher in cultured untreated MDMs from SSc-ILD pts compared to MDMs without ILD (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05; <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1\u00b5M significantly downregulated the gene expression and protein synthesis of CD204, CD206, CD163 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), and MerTK (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) compared to untreated cells after 24\u00a0h of treatment. Limited to MerTK and IL10, both nintedanib concentrations significantly downregulated their gene expression already after 16\u00a0h of treatment (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). In cultured SSc-ILD MDMs, nintedanib 0.1 and 1\u00b5M significantly reduced the release of active TGF\u03b21 after 24\u00a0h of treatment (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 vs. untreated cells).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In cultured MDMs from SSc-ILD pts, nintedanib seems to downregulate the profibrotic M2 phenotype through the significant reduction of gene expression and protein synthesis of M2 cell surface markers, together with the significant reduction of TGF\u03b21 release, and notably MerTK, a tyrosine kinase receptor involved in lung fibrosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13075-024-03308-7","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T06:02:30Z","timestamp":1710914550000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Nintedanib downregulates the profibrotic M2 phenotype in cultured monocyte-derived macrophages obtained from systemic sclerosis patients affected by interstitial lung disease"],"prefix":"10.1186","volume":"26","author":[{"given":"Stefano","family":"Soldano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Montagna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Gotelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Campitiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Pizzorni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Paolino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Sulli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-0932","authenticated-orcid":false,"given":"Maurizio","family":"Cutolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,3,20]]},"reference":[{"key":"3308_CR1","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/S0140-6736(22)01692-0","volume":"401","author":"ER Volkmann","year":"2023","unstructured":"Volkmann ER, Andr\u00e9asson K, Smith V. 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