Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Blood. 2023 Aug 10;142(6):589-606. doi: 10.1182/blood.2022019145.
Neutrophils reside in the bone marrow (BM), ready for deployment to sites of injury/infection, initiating inflammation and its resolution. Here, we report that distal infections signal to the BM via resolvins to regulate granulopoiesis and BM neutrophil deployment. Emergency granulopoiesis during peritonitis evoked changes in BM resolvin D1 (RvD1) and BM RvD4. We found that leukotriene B4 stimulates neutrophil deployment. RvD1 and RvD4 each limited neutrophilic infiltration to infections, and differently regulated BM myeloid populations: RvD1 increased reparative monocytes, and RvD4 regulated granulocytes. RvD4 disengaged emergency granulopoiesis, prevented excess BM neutrophil deployment, and acted on granulocyte progenitors. RvD4 also stimulated exudate neutrophil, monocyte, and macrophage phagocytosis, and enhanced bacterial clearance. This mediator accelerated both neutrophil apoptosis and clearance by macrophages, thus expediting the resolution phase of inflammation. RvD4 stimulated phosphorylation of ERK1/2 and STAT3 in human BM-aspirate-derived granulocytes. RvD4 in the 1 to 100 nM range stimulated whole-blood neutrophil phagocytosis of Escherichia coli. RvD4 increased BM macrophage efferocytosis of neutrophils. Together, these results demonstrate the novel functions of resolvins in granulopoiesis and neutrophil deployment, contributing to the resolution of infectious inflammation.
中性粒细胞存在于骨髓（BM）中，随时准备部署到损伤/感染部位，引发炎症及其消退。在这里，我们报告说远处感染通过解析素来向 BM 发出信号，以调节粒细胞生成和 BM 中性粒细胞的部署。腹膜炎时紧急的粒细胞生成引起了 BM 中解析素 D1（RvD1）和 BM 中 RvD4 的变化。我们发现白三烯 B4 刺激中性粒细胞的迁移。RvD1 和 RvD4 各自限制了中性粒细胞向感染部位的浸润，并以不同的方式调节 BM 髓样细胞群体：RvD1 增加了修复性单核细胞，而 RvD4 调节了粒细胞。RvD4 解除了紧急粒细胞生成，防止了 BM 中性粒细胞的过度迁移，并作用于粒细胞祖细胞。RvD4 还刺激渗出液中性粒细胞、单核细胞和巨噬细胞的吞噬作用，并增强了细菌清除能力。这种介质加速了中性粒细胞的凋亡和巨噬细胞的清除，从而加速了炎症的消退阶段。RvD4 刺激了人 BM 抽吸物衍生的粒细胞中 ERK1/2 和 STAT3 的磷酸化。RvD4 在 1 到 100 nM 范围内刺激全血中性粒细胞对大肠杆菌的吞噬作用。RvD4 增加了 BM 巨噬细胞对中性粒细胞的吞噬作用。总之，这些结果表明解析素在粒细胞生成和中性粒细胞迁移中的新功能，有助于感染性炎症的消退。
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