Granulocyte Apoptosis and Its Role in the Resolution and Control of Lung Inflammation

Elucidation of the poorly understood mechanisms by which acute inflammation normally resolves is likely to provide new insights into the pathogenesis of persistent inflammatory states that characterize inflammatory disease and generate new therapeutic targets. We have concentrated on the mechanisms by which granulocytes and their histotoxic contents are cleared from inflamed sites during resolution. Although it had been assumed that extravasated neutrophils disintegrated (undergo necrosis) in situ, we have demonstrated an alternative fate, whereby the cell undergoes apoptosis, a process that has different implications for the control of inflammation. During apoptosis the neutrophil retains its granule contents and loses the ability to secrete them in response to secretagogues. In contrast to necrotic neutrophils, apoptotic neutrophils are ingested by inflammatory macrophages employing novel phagocytic recognition mechanisms that fail to provoke a macrophage proinflammatory response. These recognition mechanisms can be modulated by a number of environmental factors and may represent a pivotal point in the control of inflammation, since if apoptotic granulocytes are not rapidly cleared they undergo secondary necrosis with all the detrimental consequences entailed. The apoptotic clearance pathway is also available to eosinophil granulocytes, but our work suggests that the internal controls may be different from those in neutrophils. For example, corticosteroids delay neutrophil apoptosis but greatly accelerate eosinophil apoptosis, in what may represent a previously unsuspected beneficial mechanism of steroid action in allergic diseases such as bronchial asthma. Furthermore, such differences may lead to novel therapies based on the specific induction of eosinophil apoptosis. Haslett C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation.