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We undertook this study to characterize the activation profile of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c monocyte\u2010derived macrophages and assessed their interaction with <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma and peripheral blood mononuclear cells (<jats:styled-content style=\"fixed-case\">PBMC<\/jats:styled-content>s) were obtained from whole blood from <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients (n = 24) and age\u2010 and sex\u2010matched healthy controls (n = 12). Monocytes were cultured with autologous or allogeneic plasma to differentiate cells into macrophages. For reciprocal activation studies, macrophages were cocultured with fibroblasts using Transwell plates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The gene expression signature associated with blood\u2010derived human <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages was enriched in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c skin in an independent cohort and correlated with skin fibrosis. <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages expressed surface markers associated with activation and released <jats:styled-content style=\"fixed-case\">CCL<\/jats:styled-content>2, interleukin\u20106, and transforming growth factor \u03b2 under basal conditions (n = 8) (<jats:italic>P<\/jats:italic> &lt; 0.05). Differentiation of healthy donor monocytes in plasma from <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients conferred the immunophenotype of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages (n = 13) (<jats:italic>P<\/jats:italic> &lt; 0.05). Transwell experiments demonstrated that coculture of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages with <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c fibroblasts induced fibroblast activation (n = 3) (<jats:italic>P<\/jats:italic> &lt; 0.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data demonstrate that the activation profile of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages is profibrotic. <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages are activated under basal conditions and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These findings also suggest that activation of <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c macrophages arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c and suggest that therapeutic targeting of these cells may be beneficial in ameliorating disease in <jats:styled-content style=\"fixed-case\">SS<\/jats:styled-content>c patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41243","type":"journal-article","created":{"date-parts":[[2020,3,5]],"date-time":"2020-03-05T06:13:41Z","timestamp":1583388821000},"page":"1160-1169","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Profibrotic Activation of Human Macrophages in Systemic Sclerosis"],"prefix":"10.1002","volume":"72","author":[{"given":"Rajan","family":"Bhandari","sequence":"first","affiliation":[{"name":"Geisel School of Medicine at Dartmouth Lebanon New 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