{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:03:16Z","timestamp":1792782196913,"version":"4.5.0"},"reference-count":33,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T00:00:00Z","timestamp":1448409600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Chinese Natural Science Foundation","award":["81072503"],"award-info":[{"award-number":["81072503"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Neutrophil extracellular traps (NETs) have been shown to play an important role in systemic lupus erythematosus (SLE) pathogenesis by activating plasmacytoid dendritic cells (PDCs) and the type I interferon (IFN) pathway. NETs composed of self\u2010DNA are considered to be of nuclear origin and are a major source of anti\u2010DNA autoantibody generation. This study was undertaken to evaluate whether mitochondrial DNA (mtDNA) resides in NETs, to evaluate whether mtDNA and anti\u2010mtDNA antibodies cause dysregulation of the PDC\u2013IFN\u03b1 pathway, and to investigate the clinical implication in SLE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with SLE (n\u2009=\u2009102), patients with rheumatoid arthritis (n\u2009=\u200930), and healthy donors (n\u2009=\u200940) were enrolled in in vitro studies. NETs were generated from phorbol 12\u2010myristate 13\u2010acetate (PMA)\u2013stimulated peripheral neutrophils. Immunofluorescence staining was used to detect NET formation ex vivo and in lupus nephritis renal biopsy samples. The mtDNA levels and type I IFN\u2013inducible gene scores were measured by quantitative polymerase chain reaction. Anti\u2010mtDNA antibodies, anti\u2013double\u2010stranded DNA (anti\u2013dsDNA) antibodies, and IFN\u03b1 were detected by enzyme\u2010linked immunosorbent assay. Purified PDCs were stimulated by isolated NETs, mtDNA, or dsDNA, combined with anti\u2010mtDNA or dsDNA IgG, or other culture conditions. Additional patients with SLE (n\u2009=\u2009113) were enrolled in a proof\u2010of\u2010concept trial. We evaluated the efficacy and safety of metformin on a background of corticosteroids and conventional immunosuppressive agents in patients with mild or moderate lupus. The primary end point was the efficacy of metformin for reducing disease flare.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We detected mtDNA in NETs, and anti\u2010mtDNA antibody levels were elevated in SLE patients compared with controls and significantly correlated with IFN scores and the disease activity index. The presence of anti\u2010mtDNA antibodies was disproportionately associated with lupus nephritis, and correlated better than anti\u2010dsDNA antibody levels with the lupus nephritis activity index. Mitochondrial DNA was deposited in NETs in lupus nephritis renal biopsy specimens. In addition, mtDNA\/anti\u2010mtDNA were greater inducers of PDC IFN\u03b1 production via Toll\u2010like receptor engagement than dsDNA\/anti\u2010dsDNA. We assessed the effect of metformin on down\u2010regulating the NET mtDNA\u2013PDC\u2013IFN\u03b1 pathway. Metformin decreased PMA\u2010induced NET formation and CpG\u2010stimulated PDC IFN\u03b1 generation. A proof\u2010of\u2010concept trial of metformin add\u2010on treatment of mild or moderate SLE resulted in decreases in clinical flares, prednisone exposure, and body weight.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings establish a link between mtDNA in NETs, anti\u2010mtDNA antibodies, and PDC IFN\u03b1 pathogenesis in SLE, and highlight that specific strategies to down\u2010regulate this pathway, such as treatment with metformin, may be new approaches to treat SLE.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.39296","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T20:34:59Z","timestamp":1438806899000},"page":"3190-3200","source":"Crossref","is-referenced-by-count":306,"title":["Neutrophil Extracellular Trap Mitochondrial DNA and Its Autoantibody in Systemic Lupus Erythematosus and a Proof\u2010of\u2010Concept Trial of Metformin"],"prefix":"10.1002","volume":"67","author":[{"given":"Haiting","family":"Wang","sequence":"first","affiliation":[{"name":"Renji Hospital South Campus and Shanghai JiaoTong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Li","sequence":"additional","affiliation":[{"name":"Renji Hospital South Campus and Shanghai JiaoTong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Renji Hospital South Campus and Shanghai JiaoTong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueying","family":"Gu","sequence":"additional","affiliation":[{"name":"Renji Hospital South Campus and Shanghai JiaoTong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Ye","sequence":"additional","affiliation":[{"name":"Renji Hospital South Campus and Shanghai JiaoTong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,25]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60954-X"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001201"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3001180"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.6.3296"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23025"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.96"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.9.3799"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/35047123"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.161293498"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08780"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20110386"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2012.10.011"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1710"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200606027"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400928"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780350606"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1191\/096120300672904669"},{"key":"e_1_2_7_19_1","volume-title":"Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. 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