Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
BioMEMS Resource Center, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, MA; and.
Blood. 2022 Feb 24;139(8):1222-1233. doi: 10.1182/blood.2021013422.
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.
新鉴定的 13 系列（T 系列） resolvins（RvTs）调节吞噬细胞功能并加速感染性炎症的消退。由于严重急性呼吸综合征冠状病毒 2 引起涉及中性粒细胞胞外陷阱（NETs）的失控炎症，我们测试了立体化学定义的 RvTs 是否调节 NET 形成。使用微流控装置在佛波醇 12-肉豆蔻酸 13-乙酸刺激的人全血中捕获 NETs，RvTs（每种 2.5 nM）强烈减少 NETs。用白细胞介素-1β刺激的人中性粒细胞，每种 RvT 剂量和时间依赖性地降低 NETosis，与已知的 NETosis 抑制剂（10 μM）相比，在 10 nM 时具有约 50%的效力。在金黄色葡萄球菌感染的小鼠中，RvTs（每种 50 ng）限制中性粒细胞浸润、细菌滴度和 NETs。此外，每种 RvT 增强人巨噬细胞对 NET 的摄取；RvT2 是四种 RvTs 中最有效的，使 NET 吞噬作用增加超过 50%。作为细胞内信号转导机制的一部分，RvT2 增加了人巨噬细胞中的环腺苷酸单磷酸和磷酸 AMP 激活蛋白激酶（AMPK），并且 RvT2 刺激的 NET 摄取被蛋白激酶 A 和 AMPK 抑制所消除。RvT2 还刺激体内小鼠巨噬细胞清除 NET。总之，这些结果为 RvTs 的新型抗炎作用提供了证据，即通过环腺苷酸单磷酸-蛋白激酶 A-AMPK 轴减少 NETosis 并增强巨噬细胞 NET 清除。因此，RvTs 为在感染期间调节 NET 介导的继发组织损伤以及监测 NETs 提供了机会。
