title: Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis. A caspase-independent cell clearance program.
abstract: Apoptosis is a physiological program for the deletion of cells in which caspases govern events leading to safe clearance by phagocytes. However, a growing weight of evidence now suggests that not all forms of programmed cell death are caspase-dependent. We now report a complete and constitutive but caspase-independent program for the specific phagocytic clearance of intact effete platelets, anucleated blood cells of critical importance in health and disease. Platelets aged in vitro not only exhibited increased expression of proapoptotic Bak and Bax but also evidenced constitutive diminution of function such as decreased aggregation to ADP, which was accelerated by culture in the absence of plasma. This abrogation of cell function in plasma-deprived platelets was associated with morphological and biochemical features similar to those of granulocyte apoptosis, that is, cytoplasmic condensation, plasma membrane changes including exposure of phosphatidylserine and the granule protein P-selectin, and recognition by phagocyte scavenger receptors. However, and in contrast with constitutive death of other inflammatory blood cells by apoptosis, these events were not affected by caspase inhibitors, nor was there evidence of caspase-3 activation either by hydrolysis of analog peptide substrates or Western blot analysis, serving to emphasize that neither programmed cell death nor clearance by phagocytes need involve caspases.
authors.affiliation: Centre for Inflammation Research, Department of Clinical Sciences, Royal Infirmary, Edinburgh, EH3 9YW. Simon.Brown@ed.ac.uk
authors.forename: S B
authors.initials: SB
authors.lastname: Brown
authors.forename: M C
authors.initials: MC
authors.lastname: Clarke
authors.forename: L
authors.initials: L
authors.lastname: Magowan
authors.forename: H
authors.initials: H
authors.lastname: Sanderson
authors.forename: J
authors.initials: J
authors.lastname: Savill
mesh_terms: D017209:Apoptosis; D001792:Blood Platelets / Q000473:pathology* / Q000648:ultrastructure; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008854:Microscopy, Electron; D009000:Monocytes / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D010949:Plasma / Q000378:metabolism; D010974:Platelet Aggregation; D011480:Protease Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D013997:Time Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494772:BAK1 protein, human; C494826:BAX protein, human; D008565:Membrane Proteins; D019007:P-Selectin; D010718:Phosphatidylserines; D011480:Protease Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D003094:Collagen; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases