Granulocyte apoptosis and the control of inflammation.
We have described a novel pathway available for the clearance of extravasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, a process which leads to their phagocytosis by inflammatory macrophages. By contrast with necrosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would tend to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for macrophage recognition of senescent neutrophils with intact cell membranes which exclude vital dyes and retain their potentially histotoxic granule contents; (ii) the apoptotic neutrophil loses its ability to secrete granule enzymes on deliberate external stimulation; (iii) the macrophage possesses a huge phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil contents; and (iv) the macrophage utilizes a novel phagocytic recognition mechanism which fails to trigger the release of pro-inflammatory macrophage mediators during the phagocytosis of apoptotic neutrophils. Preliminary characterization of the recognition mechanism implicates the integrin alpha v beta 3 (vitronectin receptor) and CD36 (thrombospondin receptor) on the macrophage surface. Macrophage phagocytosis of apoptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifically modulated by external cytokines and intracellular second messenger systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, granulocyte apoptosis, with its potential for modulation by external mediators, is likely to play a key dynamic role in the control of the 'tissue load' of granulocytes at inflamed sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Haslett
C
C
Department of Medicine (RIE), University of Edinburgh Royal Infirmary, U.K.
Savill
J S
JS
Whyte
M K
MK
Stern
M
M
Dransfield
I
I
Meagher
L C
LC
D017209:Apoptosis / Q000502:physiology*; D016207:Cytokines / Q000502:physiology; D006098:Granulocytes / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology*; D008264:Macrophages / Q000502:physiology; D008854:Microscopy, Electron; D010587:Phagocytosis
D016207:Cytokines