Granulocyte Apoptosis and Macrophage Clearance of Apoptotic Cells as Targets for Pharmacological Intervention in Inflammatory Diseases

A subset of leukocytes, known as the granulocytes, are the body's first line of innate immune defense. The granulocytes are comprised of neutrophils, eosinophils and basophils of which the former two will be the focus of this review. Neutrophils defend the body against bacterial and fungal infection whilst eosinophils are thought to defend against parasitic invasions. Granulocytes are recruited to the site of infection or tissue damage where their relatively short half-life can be extended by regulatory external factors including hypoxic environments or agents that activate signaling pathways, such as NF-kB which is implicated in the up-regulation of anti-apoptotic genes. Granulocytes release various proteins, proteolytic enzymes and toxic oxygen products into the phagolysosome or surrounding environment destroying the invading organism. However, in order for inflammation to be resolved it is essential that granulocytes die by apoptosis and are phagocytosed by macrophages in a non-inflammatory fashion. This prevents the release of the cell's histotoxic contents into the extracellular milieu thereby reducing the potential for tissue damage. In instances when granulocytes fail to appropriately enter apoptosis or a defect in phagocytic clearance occurs the inflammatory response can be perpetuated, potentially resulting in the development and promotion of inflammatory disorders such as asthma or rheumatoid arthritis. Thus, selective enhancement of apoptosis and augmentation of macrophage clearance could allow targeting of inflammatory resolution to provide potential novel therapeutic agents for the treatment of inflammatory disorders.