Programmed neutrophil apoptosis and initiation of resolution. (A) When the role of neutrophils in inflamed sites ends, they remain or reverse migrate into other organs (bone marrow, lungs, and spleen; not shown) and undergo programmed cell death (apoptosis). (B) Apoptotic neutrophils expose phosphatidylserine as an eat-me signal, so that macrophages (Mφ), dendritic cells (DC), and monocytes can recognize an apoptotic body and initiate efferocytosis. (C) Clearance of an apoptotic body changes the phenotype of efferocytic cells and induces the expression of immune-modulatory lipids called specialized pro-resolving mediators (SPMs). The efferocytosis and subsequent activation with resolvin D1 (RvD1), lipoxin A4 (LXA4), and TGF-β accelerate removal of cellular debris and restore normal tissue/immune homeostasis. (D) Induction of immune modulatory T cells, Foxp3+ Treg and IL-10-producing CD4+Foxp3− Tr1. IL-10-educated neutrophils become apoptotic and help tissue repair. (E) The efferocytosis of apoptotic neutrophils in the bone marrow decreases the IL-23/IL-17a-G-CSF axis and restores normal state of granulopoiesis.
