Phagocytosis of apoptotic cells by neutrophil granulocytes: Diminished proinflammatory neutrophil functions in the presence of apoptotic cells

Neutrophil granulocytes are rapidly recruited fromthe bloodstream to the site of acute inflammation where they die in large numbers. Because release of toxic substances fromdeadneutrophilscan propagate theinflammatory response leadingto tissue destruction, clearance of dying inflammatory neutrophils hasa critical function in the resolutionof the inflammatory response. Apoptotic neutrophils are phagocytosed primarily by macrophages, provided these cells are present in adequate numbers. However,macrophages are rare at sites of acute inflammation, whereas the number of neutrophils can be extremely high. In the current study, invitro experiments with human neutrophils were carried out to investigate whether neutrophils can ingest apoptotic neutrophils. We show that naïve granulocytes isolated fromvenous blood have a limited capacity to phagocytose apoptotic cells. However, exposure to activating stimuli such as LPS, GM-CSF and/or IFN-γ results in enhanced phagocytosis of apoptotic cells. The efficient uptake of apoptotic cells by neutrophils was found to depend on the presence of heat labile serum factors. Importantly, the contact to or uptake of apoptotic cells inhibited neutrophil functions such as respiratory burst and the release of the proinflammatory cytokines TNF-α and interferon-inducible protein-10. Contact to apoptotic cells, however, induced the secretion of IL-8 and growth-related oncogene-α, which was independent of NF-κB and p38 MAPK but involved C5a and the ERK1/2 pathway. The data suggest that activated neutrophils participate in the clearance of apoptotic cells. In addition, because apoptotic cells inhibit proinflammatory functions of neutrophils, uptake of apoptotic cells by neutrophils contributes to the resolution of inflammation.