{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:08:51Z","timestamp":1792843731827,"version":"4.5.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Systemic sclerosis (SSc) is a multiple-organ disease characterized by vascular damage, autoimmunity, and tissue fibrosis. Organ injuries such as interstitial lung diseases (ILD), resulting from inflammatory and fibrosis processes, lead to poor prognosis. Although autoantibodies are detected in the serum of patients with SSc, the mechanisms by which immune cells are involved in tissue inflammation and fibrosis is not fully understood. Recent studies have revealed carcinoembryonic antigen related cell adhesion molecule (CEACAM)-positive monocytes are involved in murine bleomycin-induced lung fibrosis. We investigated CEACAM-positive monocytes in patients with SSc to clarify the role of monocytes in the pathogenesis of SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The proportion of of CEACAM-positive classical monocytes in healthy controls (HCs) and patients with rheumatoid arthritis (RA) and SSc was evaluated using flow cytometry. The correlation between the proportion of CEACAM-positive monocytes and clinical parameters was analyzed in patients with SSc. Gene expression microarrays were performed in CEACAM-positive and negative monocytes in patients with SSc. Infiltration of CEACAM-positive monocytes into scleroderma skin was evaluated by immunohistochemical staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The proportion of CEACAM-positive classical monocytes was increased in patients with early SSc within 2 years after diagnosis, which positively correlated with ESR, serum IgG, and serum KL-6 and negatively correlated with %forced vital capacity. The percentage of CEACAM-positive monocytes decreased after immunosuppressive therapy. CEACAM6-positive cells among classical monocytes were significantly increased in patients with SSc compared with HCs and patients with rheumatoid arthritis. SSc serum induced CEACAM6 expression on monocytes from HCs. Functionally, CEACAM-positive monocytes produced higher levels of TNF-\u03b1 and IL-1\u03b2 compared to CEACAM-negative cells and showed activation of the NF-\u03baB pathway. Furthermore, CEACAM6-positive monocytes infiltrated the dermis of SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>CEACAM-positive monocytes showed inflammatory phenotypes and may be involved in the tissue inflammation and fibrosis in early SSc. CEACAM-positive monocytes may be one of biomarkers to detect patients with progressive ILD, requiring therapeutic intervention.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1016914","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T11:10:47Z","timestamp":1666264247000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["CEACAM 1, 3, 5 and 6 -positive classical monocytes correlate with interstitial lung disease in early systemic sclerosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Kana","family":"Yokoyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Mitoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Kawano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yamauchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaolei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Ayano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutaka","family":"Kimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Ono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yojiro","family":"Arinobu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Akashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiko","family":"Horiuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Niiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1080\/1744666x.2019.1614915","article-title":"Pathophysiology of systemic sclerosis: Current understanding and new insights","volume":"15","author":"Cutolo","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.mvr.2017.08.004","article-title":"Correlations between blood perfusion and dermal thickness in different skin areas of systemic sclerosis patients","volume":"115","author":"Ruaro","year":"2018","journal-title":"Microvasc Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(17)30933-9","article-title":"Systemic sclerosis","volume":"390","author":"Denton","year":"2017","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2687","DOI":"10.3390\/jcm9092687","article-title":"The pathogenesis of systemic sclerosis: An understanding based on a common pathologic cascade across multiple organs and additional organ-specific pathologies","volume":"9","author":"Asano","year":"2020","journal-title":"J Clin Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.3390\/jcm11092299","article-title":"Systemic scleroderma-definition, clinical picture and laboratory diagnostics","volume":"11","author":"Kowalska-K\u0119pczy\u0144ska","year":"2022","journal-title":"J Clin Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2147\/jir.S82320","article-title":"The macrophages in rheumatic diseases","volume":"9","author":"Laria","year":"2016","journal-title":"J Inflamm Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1007\/s12016-017-8606-7","article-title":"Myeloid populations in systemic autoimmune diseases","volume":"53","author":"Morell","year":"2017","journal-title":"Clin Rev Allergy Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.coi.2021.07.007","article-title":"Signals governing monocyte differentiation during inflammation","volume":"73","author":"Orozco","year":"2021","journal-title":"Curr Opin Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-019-04315-7","article-title":"Correlation between circulating fibrocytes and dermal thickness in limited cutaneous systemic sclerosis patients: A pilot study","volume":"39","author":"Ruaro","year":"2019","journal-title":"Rheumatol Int"},{"key":"B10","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s13075-020-02376-9","article-title":"Long non-coding rna hotair induces Gli2 expression through notch signalling in systemic sclerosis dermal fibroblasts","volume":"22","author":"Wasson","year":"2020","journal-title":"Arthritis Res Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/bor.0000000000000835","article-title":"Contribution of monocytes and macrophages to the pathogenesis of systemic sclerosis: Recent insights and therapeutic implications","volume":"33","author":"Lescoat","year":"2021","journal-title":"Curr Opin Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01140","article-title":"The role of monocytes and macrophages in autoimmune diseases: A comprehensive review","volume":"10","author":"Ma","year":"2019","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033508","article-title":"Differentiation potential of Cd14+ monocytes into myofibroblasts in patients with systemic sclerosis","volume":"7","author":"Binai","year":"2012","journal-title":"PloS One"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-201958","article-title":"Toll-like receptor-mediated, enhanced production of profibrotic timp-1 in monocytes from patients with systemic sclerosis: Role of serum factors","volume":"72","author":"Ciechomska","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B15","doi-asserted-by":"publisher","first-page":"R128","DOI":"10.1186\/ar3066","article-title":"Characterization of Monocyte\/Macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis","volume":"12","author":"Higashi-Kuwata","year":"2010","journal-title":"Arthritis Res Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/art.22382","article-title":"A macrophage marker, siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists","volume":"56","author":"York","year":"2007","journal-title":"Arthritis Rheum"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213648","article-title":"Increase in circulating cells coexpressing M1 and M2 macrophage surface markers in patients with systemic sclerosis","volume":"77","author":"Soldano","year":"2018","journal-title":"Ann Rheum Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-018-0891-z","article-title":"A circulating cell population showing both M1 and M2 Monocyte\/Macrophage surface markers characterizes systemic sclerosis patients with lung involvement","volume":"19","author":"Trombetta","year":"2018","journal-title":"Respir Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.642891","article-title":"Elevated fibronectin levels in profibrotic Cd14(+) monocytes and Cd14(+) macrophages in systemic sclerosis","volume":"12","author":"Rudnik","year":"2021","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/s2213-2600(18)30508-3","article-title":"Increased monocyte count as a cellular biomarker for poor outcomes in fibrotic diseases: A retrospective, multicentre cohort study","volume":"7","author":"Scott","year":"2019","journal-title":"Lancet Respir Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nature20611","article-title":"Identification of an atypical monocyte and committed progenitor involved in fibrosis","volume":"541","author":"Satoh","year":"2017","journal-title":"Nature"},{"key":"B22","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.cytogfr.2019.05.008","article-title":"Carcinoembryonic antigen (Ceacam) family members and inflammatory bowel disease","volume":"47","author":"Kelleher","year":"2019","journal-title":"Cytokine Growth Factor Rev"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608864200","article-title":"Ceacam1 (Cd66a) promotes human monocyte survival Via a phosphatidylinositol 3-kinase- and akt-dependent pathway","volume":"281","author":"Yu","year":"2006","journal-title":"J Biol Chem"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098","article-title":"2013 Classification criteria for systemic sclerosis: An American college of Rheumatology\/European league against rheumatism collaborative initiative","volume":"65","author":"van den Hoogen","year":"2013","journal-title":"Arthritis Rheum"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01070","article-title":"Human monocyte subset distinctions and function: Insights from gene expression analysis","volume":"11","author":"Cormican","year":"2020","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/s1568-9972(01)00002-7","article-title":"Pathogenic effects of anti-fc gamma receptor iiib (Cd16) on polymorphonuclear neutrophils in non-Organ-Specific autoimmune diseases","volume":"1","author":"Youinou","year":"2002","journal-title":"Autoimmun Rev"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-6-78","article-title":"Interdependency of ceacam-1, -3, -6, and -8 induced human neutrophil adhesion to endothelial cells","volume":"6","author":"Skubitz","year":"2008","journal-title":"J Transl Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101296","article-title":"Ceacam1 structure and function in immunity and its therapeutic implications","volume":"42","author":"Kim","year":"2019","journal-title":"Semin Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.03.009","article-title":"Novel mouse model for carcinoembryonic antigen-based therapy","volume":"9","author":"Chan","year":"2004","journal-title":"Mol Ther"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811x-12-27","article-title":"Signaling by epithelial members of the ceacam family - mucosal docking sites for pathogenic bacteria","volume":"12","author":"Tchoupa","year":"2014","journal-title":"Cell Commun Signal"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1509511112","article-title":"Diverse oligomeric states of ceacam igv domains","volume":"112","author":"Bonsor","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","article-title":"Treatment of early diffuse cutaneous systemic sclerosis patients in Japan by low-dose corticosteroids for skin involvement","volume":"22","author":"Takehara","year":"2004","journal-title":"Clin Exp Rheumatol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1186\/s13063-018-2798-x","article-title":"Hit hard and early: Analysing the effects of high-dose methylprednisolone on nailfold capillary changes and biomarkers in very early systemic sclerosis: Study protocol for a 12-week randomised controlled trial","volume":"19","author":"van den Hombergh","year":"2018","journal-title":"Trials"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02028","article-title":"More than suppression: Glucocorticoid action on monocytes and macrophages","volume":"10","author":"Ehrchen","year":"2019","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.037887","article-title":"Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration","volume":"12","author":"Xie","year":"2019","journal-title":"Dis Model Mech"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2010.09.015","article-title":"Fibrosis in systemic sclerosis: Emerging concepts and implications for targeted therapy","volume":"10","author":"Wei","year":"2011","journal-title":"Autoimmun Rev"},{"key":"B37","article-title":"The role of inflammatory markers in assessment of disease activity in systemic sclerosis","author":"Ross","year":"2018","journal-title":"Clin Exp Rheumatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2003.55.135","article-title":"Expression of Ceacam6 in resectable colorectal cancer: A factor of independent prognostic significance","volume":"21","author":"Jantscheff","year":"2003","journal-title":"J Clin Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4238\/2014.September.26.6","article-title":"Expression profiling of Ceacam6 associated with the tumorigenesis and progression in gastric adenocarcinoma","volume":"13","author":"Deng","year":"2014","journal-title":"Genet Mol Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2230.2007.02678.x","article-title":"Elevation of igg levels is a serological indicator for pulmonary fibrosis in systemic sclerosis with anti-topoisomerase I antibodies and those with anticentromere antibody","volume":"33","author":"Komura","year":"2008","journal-title":"Clin Exp Dermatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.15079","article-title":"Rituximab therapy is more effective than cyclophosphamide therapy for Japanese patients with anti-topoisomerase I-positive systemic sclerosis-associated interstitial lung disease","volume":"46","author":"Ebata","year":"2019","journal-title":"J Dermatol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/cas.13437","article-title":"Towards understanding the mechanisms of actions of carcinoembryonic antigen-related cell adhesion molecule 6 in cancer progression","volume":"109","author":"Rizeq","year":"2018","journal-title":"Cancer Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24748","article-title":"Akt-mediated regulation of nfkappab and the essentialness of nfkappab for the oncogenicity of Pi3k and akt","volume":"125","author":"Bai","year":"2009","journal-title":"Int J Cancer"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/jci30504","article-title":"CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease","volume":"117","author":"Barnich","year":"2007","journal-title":"J Clin Invest"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1016914\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T11:10:53Z","timestamp":1666264253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1016914\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2022.1016914"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1016914","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,20]]},"article-number":"1016914"}}