{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:24:30Z","timestamp":1790745870829,"version":"4.1.0"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_152876\/1, 310030_175663"],"award-info":[{"award-number":["310030_152876\/1, 310030_175663"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004362","name":"Schweizerische Herzstiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>\n                      Immunohistochemistry analysis showed accumulation of CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (\u03b1SMA)-positive fibroblasts, CD68\n                      <jats:sup>+<\/jats:sup>\n                      and mannose-R\n                      <jats:sup>+<\/jats:sup>\n                      macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14\n                      <jats:sup>+<\/jats:sup>\n                      blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated\n                      <jats:italic>FN1<\/jats:italic>\n                      (gene encoding fibronectin) expression and TGF-\u03b2 signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14\n                      <jats:sup>+<\/jats:sup>\n                      pulmonary macrophages demonstrated activated profibrotic signature with the elevated\n                      <jats:italic>FN1<\/jats:italic>\n                      expression in SSc patients with interstitial lung disease. Peripheral blood CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-\u03b2, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and \u03b1SMA. In addition, CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-\u03b2 signalling pathway with SD208 (TGF-\u03b2 receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-\u03b2-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes and CD14\n                      <jats:sup>+<\/jats:sup>\n                      pulmonary macrophages in SSc and highlighted the capability of CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14\n                      <jats:sup>+<\/jats:sup>\n                      monocytes\/macrophages can be considered as ECM producers in SSc pathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2021.642891","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T02:02:02Z","timestamp":1629770522000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":62,"title":["Elevated Fibronectin Levels in Profibrotic CD14+ Monocytes and CD14+ Macrophages in Systemic Sclerosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Micha\u0142","family":"Rudnik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amela","family":"Hukara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ievgeniia","family":"Kocherova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Jordan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Schniering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Milleret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ehrbar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Klingel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Feghali-Bostwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Przemys\u0142aw","family":"B\u0142yszczuk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Kania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15002","DOI":"10.1038\/nrdp.2015.2","article-title":"Systemic Sclerosis","volume":"1","author":"Allanore","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/art.11073","article-title":"Prevalence, Incidence, Survival, and Disease Characteristics of Systemic Sclerosis in a Large US Population","volume":"48","author":"Mayes","year":"2003","journal-title":"Arthritis Rheum"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-211448","article-title":"Mapping and Predicting Mortality From Systemic Sclerosis","volume":"76","author":"Elhai","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B4","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/nrrheum.2011.149","article-title":"Understanding Fibrosis in Systemic Sclerosis: Shifting Paradigms, Emerging Opportunities","volume":"8","author":"Bhattacharyya","year":"2011","journal-title":"Nat Rev Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"69","DOI":"10.5301\/jsrd.5000240","article-title":"The Mighty Fibroblast and Its Utility in Scleroderma Research","volume":"2","author":"Garrett","year":"2017","journal-title":"J Scleroderma Relat Disord"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02452","article-title":"Unraveling SSc Pathophysiology; 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