中性粒细胞胞外陷阱
炎症
吞噬作用
安普克
蛋白激酶A
吞噬细胞
促炎细胞因子
佛波
生物
激酶
免疫学
细胞生物学
蛋白激酶C
作者
Nan Chiang,Miyuki Sakuma,Ana R. Rodriguez,Bernd W. Spur,Daniel Irimia,Charles N. Serhan
出处
期刊:Blood
[American Society of Hematology]
日期:2022-02-24
卷期号:139 (8): 1222-1233
被引量:23
标识
DOI:10.1182/blood.2021013422
摘要
The newly identified 13-series (T-series) resolvins (RvTs) regulate phagocyte functions and accelerate resolution of infectious inflammation. Because severe acute respiratory syndrome coronavirus 2 elicits uncontrolled inflammation involving neutrophil extracellular traps (NETs), we tested whether stereochemically defined RvTs regulate NET formation. Using microfluidic devices capturing NETs in phorbol 12-myristate 13-acetate-stimulated human whole blood, the RvTs (RvT1-RvT4; 2.5 nM each) potently reduced NETs. With interleukin-1β-stimulated human neutrophils, each RvT dose and time dependently decreased NETosis, conveying ∼50% potencies at 10 nM, compared with a known NETosis inhibitor (10 μM). In a murine Staphylococcus aureus infection, RvTs (50 ng each) limited neutrophil infiltration, bacterial titers, and NETs. In addition, each RvT enhanced NET uptake by human macrophages; RvT2 was the most potent of the four RvTs, giving a >50% increase in NET-phagocytosis. As part of the intracellular signaling mechanism, RvT2 increased cyclic adenosine monophosphate and phospho-AMP-activated protein kinase (AMPK) within human macrophages, and RvT2-stimulated NET uptake was abolished by protein kinase A and AMPK inhibition. RvT2 also stimulated NET clearance by mouse macrophages in vivo. Together, these results provide evidence for novel pro-resolving functions of RvTs, namely reducing NETosis and enhancing macrophage NET clearance via a cyclic adenosine monophosphate-protein kinase A-AMPK axis. Thus, RvTs open opportunities for regulating NET-mediated collateral tissue damage during infection as well as monitoring NETs.
科研通智能强力驱动
Strongly Powered by AbleSci AI