{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:01:06Z","timestamp":1791806466363,"version":"4.3.4"},"reference-count":25,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T00:00:00Z","timestamp":1607990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-\u03b1) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.<\/jats:p>","DOI":"10.3390\/ijms21249544","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T21:11:02Z","timestamp":1608066662000},"page":"9544","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3187-2288","authenticated-orcid":false,"given":"Tiago","family":"Carvalheiro","sequence":"first","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4954-5151","authenticated-orcid":false,"given":"Ana P.","family":"Lopes","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten","family":"van der Kroef","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Malvar-Fernandez","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-9248","authenticated-orcid":false,"given":"Carlos","family":"Rafael-Vidal","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36313 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5329-5787","authenticated-orcid":false,"given":"Anneline C.","family":"Hinrichs","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nila H.","family":"Servaas","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke","family":"Bonte-Mineur","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Maasstad Hospital Rotterdam, 3079 DZ Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2394-6926","authenticated-orcid":false,"given":"Marc R.","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Maasstad Hospital Rotterdam, 3079 DZ Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Beretta","sequence":"additional","affiliation":[{"name":"Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maili","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wioleta","family":"Marut","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Pego-Reigosa","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36313 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R. D. J.","family":"Radstake","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-2699","authenticated-orcid":false,"given":"Samuel","family":"Garcia","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht, University of Utrecht, 3508 GA Utrecht, The Netherlands"},{"name":"Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands"},{"name":"Rheumatology &amp; Immuno-mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36312 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36313 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/S0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1056\/NEJMra0806188","article-title":"Scleroderma","volume":"360","author":"Gabrielli","year":"2009","journal-title":"N. 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