Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease

Abstract

Neutrophils are the most abundant cell type involved in the innate immune response. They are rapidly recruited to sites of injury or infection where they engulf and kill invading microorganisms. Neutrophil apoptosis, the process of programmed cell death that prevents the release of neutrophil histotoxic contents, is tightly regulated and limits the destructive capacity of neutrophil products to surrounding tissue. The subsequent recognition and phagocytosis of apoptotic cells by phagocytic cells such as macrophages is central to the successful resolution of an inflammatory response and it is increasingly apparent that the dying neutrophil itself exerts an anti-inflammatory effect through modulation of surrounding cell responses, particularly macrophage inflammatory cytokine release. Apoptosis may be delayed, induced or enhanced by micro-organisms dependent on their immune evasion strategies and the health of the host they encounter. There is now an established field of research aimed at understanding the regulation of apoptosis and its potential as a target for therapeutic intervention in inflammatory and infective diseases. This review focuses on the physiological regulation of neutrophil apoptosis with respect to the innate immune system and highlights recent advances in mechanistic understanding of apoptotic pathways and their therapeutic manipulation in appropriate and excessive innate immune responses.

Fig. 1

Demonstration of neutrophil apoptosis by live-cell imaging using confocal microscopy. Neutrophil apoptosis induced by the cyclin-dependent kinase inhibitor R-roscovitine. Neutrophil with intact mitochondria fluorescing red (a). Neutrophil has rounded up (b) before blebbing occurs (c) and mitochondrial dissipation with green fluorescence throughout the cytoplasm (d). Annexin-V binding to exposed phosphatidylserine residues is shown by green fluorescence at cell periphery (e) followed by secondary necrosis with PI entering cell nucleus (f), and then spreading through the cytoplasm (g), presumably with nuclear membrane disruption.

Fig. 2

Neutrophil apoptosis. Extrinsic apoptosis as typified by apoptotic pathway triggering by TNF-α or Fas ligand (TNF-α depicted). Extrinsic apoptosis proceeds via clustering and cleavage of procaspase-8. In neutrophils (and other type II apoptotic cells) it is linked to the intrinsic apoptotic (or mitochondrial) death pathway by cleavage of the pro-apoptotic bcl-2 homologue Bid. The intrinsic pathway is initiated when the tightly regulated balance of bcl-2 homologue proteins tips in favour of pro-apoptotic proteins such as Bim, Bad, Bax and Bak. Also shown is the antiapoptotic function of TNF-α which mediates production of survival proteins via NF-κB signalling. The key anti-apoptotic Bcl-2 homologue in neutrophils is Mcl-1 which is regulated by a number of signalling pathways (created using SABIOscience presentation tools).