2021 Fiscal Year Final Research Report
Elucidation of inflammatory mechanism and development of new treatment by immunological analysis of platelet-leukocyte contact
| Project/Area Number |
18K08339
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | 炎症 / 細胞外ヒストン / Immunothrombosis / 好中球 / 血小板 / Mac-1 / 糖尿病 / 血管障害 |
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| Outline of Final Research Achievements |
It is known that extracellular histones, which is one of the acute phase proteins in inflammation, causes aggravation of organ damage by attacking endothelial cells and forming a thrombus. We demonstrated that extracellular histones activate neutrophils and platelets via the adhesion factor Mac-1 and aggregate them, contributing to thromboinflammation. It was also found that this condition is exacerbated in diabetes, in which the sensitivity of neutrophils to extracellular histones is amplified and activated neutrophils mobilized to peripheral blood by histone stimulation are significantly increased. These results suggest that extracellular histones may contribute to the aggravation of acute organ damage by causing platelet-neutrophil aggregation using Mac-1 as a key mediator in acute inflammation. In conclusion, extracellular histones transmit signals through Mac-1-dependent pathway by directly stimulating both neutrophils and platelets and promote blood coagulation and thrombosis.
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| Free Research Field |
免疫学、炎症学、血栓、腎臓学
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| Academic Significance and Societal Importance of the Research Achievements |
免疫学的機序による血栓形成メカニズムであるImmunothrombosisの制御異常により、敗血症やCOVID-19の重症化がもたらされる。Immunothrombosisのメディエータとして、傷害された細胞から放出される細胞外ヒストンは極めて重要な役割を果たす。我々は細胞外ヒストンが、接着因子Mac-1を介して好中球と血小板を凝集させて血管障害を起こすことを証明した。また、糖尿病において細胞外ヒストンに対する好中球の感受性が亢進してImmunothrombosisが増幅されて重症化することを証明し、Mac-1によるImmunothrombosisが治療の標的となる可能性を示した。
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