{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:10:05Z","timestamp":1791331805632,"version":"4.3.1"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Antineutrophil cytoplasmic antibody (ANCA)\u2013associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA\u2010mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed the role and mechanism of CypD in ANCA\u2010stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA\u2010sequencing analysis on ANCA\u2010treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD\u2010knockout mice and wild\u2010type mice using 2 different murine AAV models: anti\u2010myeloperoxidase IgG transfer\u2013induced AAV and spontaneous AAV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA\u2010induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA\u2010sequencing analyses in ANCA\u2010treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA\u2010induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD\u2010dependent opening of mitochondrial permeability transition pores is associated with ANCA\u2010induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD\u2010dependent neutrophil and endothelial necrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42314","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T13:55:14Z","timestamp":1659102914000},"page":"71-83","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase\u2010Positive Antineutrophil Cytoplasmic Antibody\u2013Associated Vasculitis"],"prefix":"10.1002","volume":"75","author":[{"given":"Takashi","family":"Kudo","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3735-4630","authenticated-orcid":false,"given":"Daigo","family":"Nakazawa","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Watanabe\u2010Kusunoki","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3468-3586","authenticated-orcid":false,"given":"Masatoshi","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of 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