Infectious Neutrophil deployment is regulated by Resolvin D4.

Neutrophils reside in 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-Resolvin D4 (RvD4). We found that Leukotriene B4 stimulated 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 acts on granulocyte progenitors. RvD4 also stimulated exudate neutrophil, monocyte and macrophage phagocytosis and enhanced bacterial clearance. This mediator accelerated both neutrophil apoptosis and their 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 1nM-100nM range stimulated whole blood neutrophil phagocytosis of E. 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.