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American Journal of Pathology, Vol 149, 911-921, Copyright © 1996 by American Society for Investigative Pathology

REGULAR ARTICLES

Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis. Mediation by alpha v beta 3/CD36/thrombospondin recognition mechanism and lack of phlogistic response

M Stern, J Savill and C Haslett
Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.

Eosinophils may mediate tissue injury in a number of allergic diseases. Previously, we reported that eosinophils constitutively undergo apoptosis (programmed cell death) in culture. As this led to phagocytosis of the intact senescent cell by macrophages, we proposed that apoptosis represented an injury-limiting eosinophil disposal mechanism. Ingestion of apoptotic neutrophils by human monocyte-derived macrophages (M phi s) was found to be mediated by adhesive interactions between thrombospondin and the M phi alpha v beta 3 vitronectin receptor integrin and M phi CD36. As this failed to elicit a pro- inflammatory response from M phi s, we sought evidence that this specific, nonphlogistic clearance mechanism may operate in eosinophil disposal. In this study, we found that M phi ingestion of apoptotic eosinophils was specifically inhibited by monoclonal antibodies to M phi alpha v beta 3, CD36, and thrombospondin and by other inhibitors of this recognition mechanism including RGD peptide and amino sugars. Furthermore, not only did M phi ingestion of intact apoptotic eosinophils fail to stimulate release of the phlogistic eicosanoid thromboxane, but there was also a lack of increased release of the pro- inflammatory cytokine granulocyte/macrophage colony-stimulating factor. However, increased release of these mediators was observed when M phi s took up senescent post-apoptotic eosinophils that had been cultured long enough to lose plasma membrane integrity. The data indicate that the nonphlogistic alpha v beta 3/CD36/thrombospondin macrophage recognition mechanism is available for clearance of intact senescent eosinophils undergoing apoptosis. Furthermore, our findings suggest that, by contrast, phagocytosis of post-apoptotic eosinophils may elicit undesirable pro-inflammatory responses.

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