Neutrophils play a central role in host defense against microbial infections and tissue injury. During severe infections, the hematopoietic system senses and rapidly adapts to the increased neutrophil demand by switching from steady-state to emergency granulopoiesis. Emergency granulopoiesis ensures de novo generation of large quantities of neutrophils from HSCs and GMPs in the bone marrow, which is critical for host survival. Excessive neutrophil production and mobilization would lead to persistent inflammation and damage to the host. Libreros et al show that distal infection increases bone marrow levels of RvD1 and RvD4, derived from a common intermediate of n-3 docosapentaenoic acid. RvD1 and RvD4 exert partially overlapping and partially distinct actions to regulate emergency granulopoiesis, and neutrophil deployment, function, and fate, at the sites of infection. In the bone marrow, RvD1 through the receptor ALX/FPR2 facilitates generation of reparative monocytes from GMPs without affecting granulopoiesis. By contrast, RvD4, acting through a yet unidentified G-protein–coupled receptor, disengages emergency granulopoiesis, inhibits leukotriene B4 (LTB4)–stimulated neutrophil deployment, accelerates apoptosis in aged neutrophils, and promotes their removal by bone marrow macrophages. RvD4 shifts granulopoiesis toward lymphopoiesis by stimulating generation of B and T lymphocytes from HSCs. At the site of infection, both RvD1 and RvD4 attenuate neutrophil influx. RvD4 enhances neutrophil phagocytosis of bacteria, neutrophil apoptosis, and efferocytosis. Efferocytotic macrophages contribute to generation of proresolving mediators, including RvD4. Thus, RvD4 (and RvD1) regulation of myelopoiesis in the bone marrow as well as bacterial clearance and the fate of neutrophils at the site of infection lead to timely resolution of infection and return to homeostasis. These would suggest the therapeutic potential for RvD4 in pathologic conditions associated with aberrant granulopoiesis and excessive neutrophil accumulation. PMN, polymorphonuclear neutrophil granulocyte. Professional illustration by Patrick Lane, ScEYEnce Studios.
