Resolution of acute inflammation and the role of apoptosis in the tissue fate of granulocytes.

We have identified a pathway for granulocyte removal in tissues which is controlled by apoptosis. This process can be modulated by agents in the inflammatory microenvironment and leads to loss of neutrophil secretory function and its phagocytosis by macrophages which utilize a novel recognition mechanism such that the macrophage does not release pro-inflammatory mediators. It is hypothesized that this represents an alternative fate to necrosis, and one which would tend to limit tissue injury and promote inflammatory resolution. This is not to suggest that granulocyte necrosis does not occur; even at sites of 'beneficial inflammation' some necrotic neutrophils may be seen. However, since the development of inflammatory disease is currently thought to result from a multifactoral, quantitative imbalance between potentially injurious inflammatory influences and tissue defences, it is reasonable to suggest that the balance between neutrophil apoptosis and necrosis could represent one of several possible pivotal points in the control of inflammation. Finally, as the specific trigger and induction processes which permit closely related cells to undergo apoptosis at markedly different rates are uncovered, it may be possible to design new anti-inflammatory therapeutic strategies directed towards causing specific cell types to 'commit suicide' and to be cleared by the mechanisms which 'nature intended'. Thus we have begun to dissect the cellular events occurring in the resolution of acute inflammation. We believe that the rapid cessation of neutrophil emigration which occurs remarkably early in the evolution of the acute inflammatory response represents one of the earliest events in the resolution process. Clearly there is much work to be done on the underlying mechanisms. These are likely to be more accessible with the recent molecular characterization of chemotactic cytokines and surface molecules involved in neutrophil-endothelial adhesion transmigration events. It is also clear that apoptosis, which represents an alternative tissue injury-limiting fate to necrosis in situ, may be important in limiting tissue injury and determining whether inflammation persists or resolves. It is also possible that there are circumstances in which the macrophage recognition and clearance of apoptotic neutrophils is impaired. However, a second glance at the events which must occur during the resolution of even the simplest model of acute inflammation (Fig. 1) is sufficient reminder that the 'surface has barely been scratched'. There remain many obscure areas, not the least of which is the fate of the inflammatory macrophage after it has completed its scavenging functions.