{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:02:11Z","timestamp":1792735331128,"version":"4.5.0"},"reference-count":53,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,10,31]],"date-time":"2022-10-31T00:00:00Z","timestamp":1667174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["The University of Pittsburgh holds a Physician\u2010Sci"],"award-info":[{"award-number":["The University of Pittsburgh holds a Physician\u2010Sci"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["2P50AR060780"],"award-info":[{"award-number":["2P50AR060780"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis\u2013associated interstitial lung disease (SSc\u2010ILD) is the leading cause of death in patients with SSc with unclear pathogenesis and limited treatment options. Evidence strongly supports an important role for profibrotic secreted phosphoprotein 1 (SPP1)\u2013expressing macrophages in SSc\u2010ILD. This study was undertaken to define the transcriptome and chromatin structural changes of SPP1 SSc\u2010ILD macrophages in order to better understand their role in promoting fibrosis and to identify transcription factors associated with open chromatin driving their altered phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed single\u2010cell RNA sequencing (scRNA\u2010Seq) on 11 explanted SSc\u2010ILD and healthy control lung samples, as well as single\u2010cell assay for transposase\u2010accessible chromatin sequencing on 5 lung samples to define altered chromatin accessibility of SPP1 macrophages. We predicted transcription factors regulating SPP1 macrophages using single\u2010cell regulatory network inference and clustering (SCENIC) and determined transcription factor binding sites associated with global alterations in SPP1 chromatin accessibility using Signac\/Seurat.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified distinct macrophage subpopulations using scRNA\u2010Seq analysis in healthy and SSc\u2010ILD lungs and assessed gene expression changes during the change of healthy control macrophages into SPP1 macrophages. Analysis of open chromatin validated SCENIC predictions, indicating that microphthalmia\u2010associated transcription factor, transcription factor EB, activating transcription factor 6, sterol regulatory element binding transcription factor 1, basic helix\u2010loop\u2010helix family member E40, Kruppel\u2010like factor 6, ETS variant transcription factor 5, and\/or members of the activator protein 1 family of transcription factors regulate SPP1 macrophage differentiation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings shed light on the underlying changes in chromatin structure and transcription factor regulation of profibrotic SPP1 macrophages in SSc\u2010ILD. Similar alterations in SPP1 macrophages may underpin fibrosis in other organs involved in SSc and point to novel targets for the treatment of SSc\u2010ILD, specifically targeting profibrotic macrophages.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42286","type":"journal-article","created":{"date-parts":[[2022,7,18]],"date-time":"2022-07-18T16:13:45Z","timestamp":1658160825000},"page":"2003-2014","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Epigenetic Regulation of Profibrotic Macrophages in Systemic Sclerosis\u2013Associated Interstitial Lung Disease"],"prefix":"10.1002","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1572-3239","authenticated-orcid":false,"given":"Anna","family":"Papazoglou","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology University of Pittsburgh  Pittsburgh 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