2021 Fiscal Year Final Research Report
Identification of platelet-madiated neutrophil extracellular traps in ANCA-associated vasculitis
| Project/Area Number |
20K22911
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2020-09-11 – 2022-03-31
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| Keywords | ANCA関連血管炎 / 好中球細胞外トラップ / 血小板 / 自然免疫 / 網羅的遺伝子発現解析 / 分子機構 / 病態解明 / 分子標的治療薬 |
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| Outline of Final Research Achievements |
Platelets from ANCA-associated vasculitis (AAV) significantly upregulated neutrophil extracellular traps (NETs) formation in vitro. Flow cytometric analysis revealed that the proportion of TLR9 positive platelets was significantly higher in ANCA-associated interstitial lung disease than HCs. CXCL4 released from TLR9 agonist stimulated platelets was significantly enhanced in AAV, which subsequently increased NETs formation. Further, neutralizing anti-CXCL4 antibody significantly inhibited NETs formation enhanced by platelets from AAV. TLR9 signaling and CXCL4 release underlie the key role that platelets play in NETs formation in the pathogenesis of AAV.
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| Free Research Field |
膠原病・アレルギー内科学
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| Academic Significance and Societal Importance of the Research Achievements |
ANCA関連血管炎は血管内皮細胞障害を伴う壊死性血管炎により、血管の閉塞や破綻、臓器障害を来たす全身性疾患で、未だ予後不良の疾患である。特に、ANCA関連間質性肺炎は生命予後不良で著効を示す治療薬が存在しない。本研究は、血小板由来液性因子であるCXCL4を阻害することで好中球細胞外トラップを抑制し、血小板を標的としたANCA関連間質性肺炎の新規分子標的治療の創薬基盤となる可能性がある。本研究で得られた知見は好中球細胞外トラップ形成の過剰の病態を呈する他疾患にも適応出来る可能性がある。
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