Nonphlogistic clearance of late apoptotic neutrophils by macrophages: Efficient phagocytosis independent of beta(2) integrins

Neutrophils undergo constitutive death by apoptosis, leading to safe nonphl ogistic phagocytosis and clearance by macrophages. Recent work has shown th at before secondary necrosis, neutrophils exhibiting classical features of apoptosis can progress to a morphologically defined late apoptotic state. H owever, whether such neutrophils could be safely cleared was unknown. We no w report that human late apoptotic neutrophils could be purified from cultu red neutrophil populations undergoing constitutive death and were subsequen tly ingested by human monocyte-derived macrophages by serum-independent mec hanisms that did not trigger the release of IL-8 or TNF-alpha. Such ingesti on was specifically inhibited by Abs to thrombospondin-1 and the alpha (v)b eta (3) vitronectin receptor. Murine bone marrow-derived macrophage phagocy tosis of late and early apoptotic neutrophils occurred by similar mechanism s, proceeding with the same efficiency as that observed for wild-type contr ols when macrophages from alpha (-/-)(m) or beta (-/-)(2) mice were used. W e conclude that specific nonphlogistic, beta (2) integrin-independent mecha nisms involving thrombospondin-1 and alpha (v)beta (3) allow macrophages to ingest late apoptotic neutrophils without eliciting inflammatory cytokine secretion.