Clearance of apoptotic neutrophils and resolution of inflammation

Abstract

The engulfment of apoptotic cells by phagocytes, a process referred to as efferocytosis, is essential for maintenance of normal tissue homeostasis and a prerequisite for the resolution of inflammation. Neutrophils are the predominant circulating white blood cell in humans, and contain an arsenal of toxic substances that kill and degrade microbes. Neutrophils are short-lived and spontaneously die by apoptosis. This review will highlight how the engulfment of apoptotic neutrophils by human phagocytes occurs, how heterogeneity of phagocyte populations influences efferocytosis signaling, and downstream consequences of efferocytosis. The efferocytosis of apoptotic neutrophils by macrophages promotes anti-inflammatory signaling, prevents neutrophil lysis, and dampens immune responses. Given the immunomodulatory properties of efferocytosis, understanding pathways that regulate and enhance efferocytosis could be harnessed to combat infection and chronic inflammatory conditions.

Keywords: apoptosis; efferocytosis; infection; inflammation; macrophages; neutrophil.

Figure 1. Examples of receptor-ligand interactions during efferocytosis of apoptotic neutrophils

Unstimulated macrophages (MΦ) primarily use receptors α_vβ₃ integrin and CD36 to efferocytose apoptotic neutrophils (PMN, A, left). Ligands on apoptotic PMN for α_vβ₃ integrin include thrombospondin (THBD) and MFG-E8, whereas ligands for CD36 likely include oxidized-LDL-like- or oxidized PS-moieties (A, left). Accessory interactions at the synapse between apoptotic PMN and unstimulated MΦ also include complement receptors CR3 and CR4 recognition of iC3b-opsonized apoptotic PMN (A, middle), and LRP-1 recognition of plasma membrane-associated CRT (A, right). Alternatively, β-glucan-stimulated MΦ recognize PS on apoptotic neutrophils via PSRs (B), and glucocorticoid-treated MΦ enhance efferocytosis through MerTK recognition of PS-bridging molecules Gas6 and Protein S (C).