Abstract
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 β2 integrins that are best known for regulating adhesion and phagocytosis. Accumulating evidence indicate that outside-in signaling through the β2 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-1-mediated phagocytosis of bacteria evokes apoptotic cell death. Mac-1 signaling is also target for the anti-inflammatory, pro-resolving mediators, including lipoxin A4, aspirin-triggered lipoxin A4, and resolvin E1. 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.
Highlights
Neutrophils form the first line of defense against invading pathogens or tissue injury
A growing body of evidence supports an important role for neutrophil apoptosis as a critical control point for the outcome of inflammation
Outside-in signaling through Mac-1 is a target for endogenous molecules, such as lipoxins, resolvin E1, and synthetic compounds to counter pro-survival and/or induce pro-apoptosis signals
Summary
Neutrophils form the first line of defense against invading pathogens or tissue injury They are rapidly recruited to the sites of infection/injury and play a prominent role in the initiation and progression of the inflammatory response. Their many defense mechanisms that destroy invading pathogens are capable of inflicting damage to the surrounding tissue (Nathan, 2006). Aged neutrophils die by constitutive (or spontaneous) apoptosis This mechanism is essential to maintain the balance of cellular homeostasis under physiological conditions (Cartwright et al, 1964; Coxon et al, 1996). Apoptosis renders neutrophils unresponsive to extracellular stimuli and leads to expression of “eat-me” signals, so that neutrophils can be recognized and removed by macrophages in the spleen and bone marrow and Kupffer cells in the liver
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