| アイテムタイプ |
学術雑誌論文 / Journal Article(1) |
| 公開日 |
2024-07-04 |
| タイトル |
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タイトル |
Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase-Positive Antineutrophil Cytoplasmic Antibody?Associated Vasculitis |
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言語 |
en |
| 言語 |
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言語 |
eng |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 著者 |
Takashi Kudo
Daigo Nakazawa
Kanako Watanabe-Kusunoki
Masatoshi Kanda
Satoka Shiratori-Aso
Nobuya Abe
Saori Nishio
Jun-Ichiro Koga
Sari Iwasaki
Takahiro Tsuji
Yuichiro Fukasawa
Miwako Yamasaki
Masahiko Watanabe
Sakiko Masuda
Utano Tomaru
Masaaki Murakami
Yasuaki Aratani
Akihiro Ishizu
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| 抄録 |
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内容記述タイプ |
Abstract |
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内容記述 |
Objective: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA-mediated 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.
Methods: We assessed the role and mechanism of CypD in ANCA-stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA-sequencing analysis on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD-knockout mice and wild-type mice using 2 different murine AAV models: anti-myeloperoxidase IgG transfer-induced AAV and spontaneous AAV.
Results: In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA-sequencing analyses in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA-induced 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-dependent opening of mitochondrial permeability transition pores is associated with ANCA-induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. |
| 書誌情報 |
Arthritis Rheumatol
巻 75,
号 1,
p. 71-83,
発行日 2022-01
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| 出版者 |
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出版者 |
Wiley |
| ISSN |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
2326-5191 |
| DOI |
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識別子タイプ |
DOI |
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関連識別子 |
10.1002/art.42314 |
