Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis - A caspase-independent cell clearance program

Apoptosis is a physiological program for the deletion of cells in which cas pases govern events leading to safe clearance by phagocytes. However, a gro wing 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 expressio n of proapoptotic Bah and Bar but also evidenced constitutive diminution of function such as decreased aggregation to ADP, which was accelerated by cu lture in the absence of plasma. This abrogation of cell function in plasma- deprived platelets was associated with morphological and biochemical featur es similar to those of granulocyte apoptosis, that is, cytoplasmic condensa tion, plasma membrane changes including exposure of phosphatidylserine and the granule protein P-selectin, and recognition by phagocyte scavenger rece ptors. However, and in contrast with constitutive death of other inflammato ry blood cells by apoptosis, these events were not affected by caspase inhi bitors, nor was there evidence of caspase-3 activation either by hydrolysis of analog peptide substrates or Western blot analysis, serving to emphasiz e that neither programmed cell death nor clearance by phagocytes need invol ve caspases.