IMPAIRMENT OF FUNCTION IN AGING NEUTROPHILS IS ASSOCIATED WITH APOPTOSIS

Neutrophil apoptosis or programmed cell death permits neutrophil recog nition and ingestion by macrophages and represents a mechanism capable of promoting resolution of inflammation. The consequences of apoptosi s for neutrophil function are the subject of these investigations. A d irect relationship between apoptosis and loss of cytoskeletal function s, phagocytosis, degranulation, and respiratory burst was demonstrated by counterflow centrifugation of neutrophils (aged for 24 h in cultur e) into fractions with varying proportions of apoptosis. Apoptotic neu trophils displayed a loss of background functions: ability to spread a nd change shape and random migration. They also showed a reduced abili ty to respond to deliberate stimulation with the receptor-dependent st imulus, FMLP, by undergoing shape change, chemotaxis, degranulation, a nd respiratory burst, and showed an inability to phagocytose opsonized zymosan. Loss of FMLP binding to apoptotic neutrophils was demonstrat ed by analysis of FML[H-3]P binding and by autoradiography. Superoxide anion production, but not shape change or degranulation response, to the receptor-independent stimulus, PMA, was preserved in apoptotic neu trophils, implying some retention of intracellular signaling pathways relevant to superoxide production. Apoptosis thus marks a loss of neut rophil functional responsiveness and defines the cell as effectively ' 'isolated'' from its external milieu. Neutrophil apoptosis may represe nt an important event in the control of inflammation, marking the neut rophil both for disposal and as a cell with profound loss of its capac ity to generate and release histotoxic products on external stimulatio n.