Mcl-1 is vital for neutrophil survival
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INTERPRETIVE SYNTHESIS REVIEW ARTICLE
Mcl-1 is vital for neutrophil survival Mark P. Murphy1,2 • Emma Caraher1,2
Ó Springer Science+Business Media New York 2015
Abstract Upon entry to the systemic circulation, neutrophils exhibit a short mean time to cell death. The viability of most cell types in a steady state is preserved by the interplay of the Bcl-2 family of proteins, wherein the anti-apoptotic members inhibit the action of their pro-apoptotic counterparts. Neutrophils, however, display absent or severely reduced expression of several anti-apoptotic Bcl-2 family proteins. Hence, they rely on the expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, for survival. This protein is uniquely short-lived relative to related proteins and its loss likely precipitates the induction of apoptosis in neutrophils. This review describes the role of Mcl-1 in the neutrophil in the context of apoptosis and highlights the proteins’ importance to the cell. We also address neutrophil apoptosis in the broader context of the cells’ response to pathogens, focussing particularly on the strategies used by pathogens to manipulate the apoptotic pathway to their own ends. Keywords Bcl-2 family proteins Caspases Host– pathogen interaction Innate immunity Neutrophil apoptosis
& Mark P. Murphy [email protected] Emma Caraher [email protected] 1
Centre for Microbial-Host Interactions, Institute of Technology Tallaght, Old Blessington Road, Tallaght, Dublin 24, Ireland
2
Centre of Applied Science for Health, Institute of Technology Tallaght, Dublin, Ireland
Introduction Inflammation is often the result of neutrophilia and has a number of undesirable sequelae. For this reason, targets to ameliorate the zeal of neutrophils can prove useful in controlling inflammation and improving health in some settings [1]. This review highlights neutrophil viability— and, specifically, the role of anti-apoptotic Mcl-1 in preserving same—as a potential focal point for modulating the cells’ activity. The resting neutrophil has a short survival time relative to other human cell types. Circulating neutrophils persist with a mean half-life generally accepted to be only 7 h in the absence of infection [2, 3]. This follows bone marrow residence of *7 days as a terminally differentiated cell [4]. This limited lifespan may be due to the unique expression profile of anti-apoptotic proteins which neutrophils exhibit. We detail in this review the cellular mechanisms of intrinsic and extrinsic cell death in neutrophils that follow from this expression, which renders the cells unusually reliant on the short-lived protein Mcl-1. Given the short lifespan of the neutrophil, the capacity of the cells to effect an anti-microbial response is enhanced by increases to their survival time. This is often mediated directly by cytokines being produced at the site of infection, such as granulocyte macrophage colony-stimulating factor (GM-CSF) [5–8]. Certain intracellular pathogens also actively enhance neutrophil viability in order to further their o
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