Transepithelial migration, necrosis and apoptosis as silent and pro-inflammatory fates of airway granulocytes

In inflammatory airway diseases, granulocytes such as eosinophils and neutrophils infiltrate the tissue where they are thought to exert pathogenic activities. To avoid a catastrophic accumulation of activated granulocytes, their recruitment must be balanced by efficient cell clearance mechanisms. In this regard, the focus has been on elimination through apoptosis and subsequent engulfment of apoptotic cells by phagocytes. However, novel data suggest that in the airways, powerful non-apoptotic mechanisms are also critically involved in cell clearance. One such mechanism is transepithelial migration into the airway lumen where the mucociliary escalator executes the final elimination. The physiological clearance of tissue granulocytes is normally silent, but can under certain situations shift to become a pro-inflammatory event. For example, apoptotic cells that escape phagocytosis, disintegrate in a pro-inflammatory process called secondary necrosis. In other situations, granulocytes are triggered to undergo an active and violent cytolytic death. This delicate balance in vivo, between silent and violent properties of granulocyte demise, complicates the design of pro-apoptotic pharmacological interventions. On the other hand, this insight may also open possibilities to new exciting treatment strategies. In this context, promoting transepithelial migration, prevention of secondary necrosis, and boosting the macrophage phagocytic system appear as exciting treatment avenues.