CD36 is required for phagocytosis of apoptotic cells by human macrophages that use either a phosphatidylserine receptor or the vitronectin receptor (alpha v beta 3).
In vivo, apoptotic cells are efficiently removed by professional or nonprofessional phagocytes, a process thought to be essential for tissue remodeling and resolution of inflammation. Macrophages recognize apoptotic cells by several mechanisms, including recognition of exposed phosphatidylserine (PS); however, PS recognition on apoptotic cells has not been identified as a feature of human macrophages. The purpose of this study was to determine whether human monocyte-derived macrophages could be stimulated to recognize PS, defined as inhibition of phagocytosis by PS-containing liposomes. We also assessed the potential roles for scavenger receptors, CD14, and lectins. Uptake of apoptotic neutrophils into unstimulated macrophages was blocked about 50% by Arg-Gly-Asp-Ser and anti-alpha(v), and up to 20% by oxidized low density lipoprotein and N-acetylglucosamine, implying a major role for integrin and minor roles for scavenger and lectin receptors. Uptake into macrophages stimulated with beta-1,3-glucan was blocked 50% by PS liposomes and 40% by oxidized low density lipoprotein, suggesting that the macrophages had switched from using integrin to recognition of PS. MEM-18 and 61D3 (anti-CD14 mAbs) were poor inhibitors of apoptotic neutrophil uptake, but good inhibitors of apoptotic lymphocyte uptake. The switch to PS recognition was accompanied by down-regulation of alpha(v)beta3 expression and function. Anti-CD36 blocked uptake into unstimulated or stimulated macrophages, suggesting CD36 involvement not only with the alpha(v)beta3 integrin mechanism (as previously reported) but also with PS recognition. A maximum of 70% inhibition was achieved by combining anti-CD36 with either anti-a(v) or PS liposomes.
Fadok
V A
VA
Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA. fadokv@njc.org
Warner
M L
ML
Bratton
D L
DL
Henson
P M
PM
D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D001426:Bacterial Proteins / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D026901:Membrane Transport Proteins; D010587:Phagocytosis / Q000276:immunology*; D010718:Phosphatidylserines / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000502:physiology*; D011975:Receptors, Mitogen / Q000502:physiology; D019030:Receptors, Vitronectin / Q000502:physiology*
D001426:Bacterial Proteins; D018955:CD36 Antigens; D018950:Lipopolysaccharide Receptors; D026901:Membrane Transport Proteins; D010718:Phosphatidylserines; D011956:Receptors, Cell Surface; D011975:Receptors, Mitogen; D019030:Receptors, Vitronectin; C066202:msrA protein, Staphylococcus epidermidis