GRANULOCYTE APOPTOSIS AND THE CONTROL OF INFLAMMATION

We have described a novel pathway available for the clearance of extra vasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would t end to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for mac rophage recognition of senescent neutrophils with intact cell membrane s which exclude vital dyes and retain their potentially histotoxic gra nule contents; (ii) the apoptotic neutrophil loses its ability to secr ete granule enzymes on deliberate external stimulation; (iii) the macr ophage possesses a hugh phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil co ntents; and (iv) the macrophage utilizes a novel phagocytic recognitio n mechanism which fails to trigger the release of pro-inflammatory mac rophage mediators during the phagocytosis of apoptotic neutrophils. Pr eliminary characterization of the recognition mechanism implicates the integrin alpha v Beta-3 (vitronectin receptor) and CD36 (thrombospond in receptor) on the macrophage surface. Macrophage phagocytosis of apo ptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifi cally modulated by external cytokines and intracellular second messeng er systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, g ranulcoyte apoptosis, with its potential for modulation by external me diators, is likely to play a key dynamic role in the control of the 't issue load' of granulocytes at inflamed sites. Further elucidation of the mechanisms and control of apoptosis in granulocytes is likely to s hed new light on the pathophysiology of inflammation and suggest new a pproaches to the therapy of inflammatory diseases.