Modulation of neutrophil apoptosis and the resolution of inflammation through β2 integrins

Precise control of the neutrophil death program provides a balance between their defense functions and safe clearance, whereas impaired regulation of neutrophil death is thought to contribute to a wide range of inflammatory pathologies. Apoptosis is essential for neutrophil functional shutdown, removal of emigrated neutrophils, and timely resolution of inflammation. Neutrophils receive survival and pro-apoptosis cues from the inflammatory microenvironment and integrate these signals through surface receptors and common downstream mechanisms. Among these receptors are the leukocyte-specific membrane receptors (32 integrins that are best known for regulating adhesion and phagocytosis. Accumulating evidence indicate that outside-in signaling through the (32 integrin Mac-1 can generate contrasting cues in neutrophils, leading to promotion of their survival or apoptosis. Binding of Mac-1 to its ligands ICAM-1, fibrinogen, or the azurophilic granule enzyme myeloperoxidase suppresses apoptosis, whereas Mac-l-mediated phagocytosis of bacteria evokes apoptotic cell death. Mac-1 signaling is also target for the anti-inflammatory, pro-resolving mediators, including lipoxin Azt, aspirin-triggered lipoxin Azt, and resolvin El. This review focuses on molecular mechanisms underlying Mac-1 regulation of neutrophil apoptosis and highlights recent advances how hierarchy of survival and pro-apoptosis signals can be harnessed to facilitate neutrophil apoptosis and the resolution of inflammation.