{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:58:16Z","timestamp":1788836296662,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["Project N\u00b0: 185300"],"award-info":[{"award-number":["Project N\u00b0: 185300"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp;amp; Rheumatology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Mitochondria are organelles with a hypomethylated circular genome. Mitochondrial DNA (mtDNA) in the systemic circulation has been implicated in inflammation. This study investigates the role of circulating DNA in systemic sclerosis (SSc) and the cellular mechanisms governing its release.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Total DNA was isolated from the plasma of healthy controls (HCs) and patients with SSc. Copy numbers were analyzed for mtDNA (ATP\u20106) and GAPDH abundance by quantitative real\u2010time polymerase chain reaction. mtDNA was isolated from HCs and patients with SSc. Neutrophils and platelets were incubated with the plasma and mtDNA of patients with SSc, and neutrophil extracellular trap (NET) formation was assessed by SytoxGreen and immunostainings. Platelets were tested for mtDNA release propensity. DNA oxidation was evaluated by MitoSOX Red staining in vitro and 8\u2010OHdG enzyme\u2010linked immunosorbent assay (ELISA) of patient plasma. Plasma interferon (IFN) type 1 and chemokine (C\u2010X\u2010C motif) ligand 4 (CXCL4) were measured by ELISA. IFN signaling activation capacity was evaluated using THP\u20101 reporter cells and confirmed by a whole blood bulk RNA transcriptomic analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Median plasma mtDNA levels were 152\u2010fold higher in patients with SSc compared with HCs, whereas nuclear DNA levels were similar. mtDNA from SSc plasma was highly oxidized. SSc\u2010derived mtDNA efficiently promoted its own release by NETosis, most potently in the neutrophils of patients with SSc and by platelet activation. Oxidized mtDNA from SSc platelets in complex with CXCL4 further stimulated mtDNA release in both neutrophils and platelets. mtDNA plasma concentrations correlated with type I IFN concentrations in the blood of patients with SSc, and SSc blood exhibited elevated IFN\u2010stimulated gene expression. SSc plasma\u2010derived mtDNA\u2010induced IFN signaling and NET formation via endosomal Toll\u2010like receptors, cyclic GMP\u2010AMP synthase\/stimulator of IFN genes, and the JAK\/STAT pathway. The type I IFN pathway further promoted NETosis and mtDNA release because IFN receptor and JAK inhibition antagonized the proNETotic effects of IFN.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>SSc plasma is characterized by highly abundant mtDNA, which drives feedback loops amplifying its own release from both neutrophils and platelets. Thus, mtDNA contributes to inflammation and tissue damage in SSc.<\/jats:p>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/art70027-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.70027","type":"journal-article","created":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T03:50:04Z","timestamp":1766116204000},"page":"1281-1293","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["A Cooperative Release of Mitochondrial\n                    <scp>DNA<\/scp>\n                    From Platelets and Neutrophils Drives an Interferon Signature in Systemic Sclerosis"],"prefix":"10.1002","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2216-9539","authenticated-orcid":false,"given":"Stavros","family":"Giaglis","sequence":"first","affiliation":[{"name":"Laboratory for Experimental Rheumatology, Department of Biomedicine University of Basel  Basel Switzerland"},{"name":"Department of Rheumatology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4506-4190","authenticated-orcid":false,"given":"Andr\u00e9 N.","family":"Tiaden","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Rheumatology, Department of Biomedicine University of Basel  Basel Switzerland"},{"name":"Department of Rheumatology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"H\u00e4ner\u2010Massimi","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Rheumatology, Department of Biomedicine University of Basel  Basel Switzerland"},{"name":"Department of Rheumatology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Kyburz","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Rheumatology, Department of Biomedicine University of Basel  Basel Switzerland"},{"name":"Department of Rheumatology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Andr\u00e9","sequence":"additional","affiliation":[{"name":"Immunology, Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Gl\u00fcck","sequence":"additional","affiliation":[{"name":"Immunology, Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Ferrero","sequence":"additional","affiliation":[{"name":"Immunology, Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart","family":"Hawtin","sequence":"additional","affiliation":[{"name":"Immunology, Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Junt","sequence":"additional","affiliation":[{"name":"Immunology, Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich A.","family":"Walker","sequence":"additional","affiliation":[{"name":"Laboratory for Experimental Rheumatology, Department of Biomedicine University of Basel  Basel Switzerland"},{"name":"Department of Rheumatology University Hospital Basel  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01692-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1114576"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13426"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.13238"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2021-002010"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4579"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kead015"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41418"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.002"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.21"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3109\/10715762.2011.645207"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2018.12.018"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00864-7"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098"},{"issue":"2","key":"e_1_2_8_17_1","first-page":"202","article-title":"Scleroderma (systemic sclerosis): classification, subsets and pathogenesis","volume":"15","author":"LeRoy EC","year":"1988","journal-title":"J Rheumatol"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e31816a6bb1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045427"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309184"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00413"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39962"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2023.117711"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09683-z"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aao3089"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217116"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keac492"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151876"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.10.001"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.15073"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.96"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar787"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00760-x"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1256478"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12710"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-80685-4"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11926-019-0815-z"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2956"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110189"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00834-4"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100085R"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36522-z"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.924899"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-022-00108-7"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2025.01.002"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19412-6"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14858"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.02.002"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.859330"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01663-z"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70027","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.70027","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70027","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T08:19:09Z","timestamp":1783930749000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.70027"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":50,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1002\/art.70027"],"URL":"https:\/\/doi.org\/10.1002\/art.70027","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]},"assertion":[{"value":"2025-07-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}