Abstract
Neutrophil granulocytes have the shortest lifespan among leukocytes in the circulation and die via apoptosis. At sites of infection or tissue injury, prolongation of neutrophil lifespan is critical for effective host defense. Apoptosis of inflammatory neutrophils and their clearance are critical control points for termination of the inflammatory response. Evasion of neutrophil apoptosis aggravates local injury and leads to persistent tissue damage. The short-lived prosurvival Bcl-2 family protein, Mcl-1 (myeloid cell leukemia-1), is instrumental in controlling apoptosis and consequently neutrophil lifespan in response to rapidly changing environmental cues during inflammation. This paper will focus on multiple levels of control of Mcl-1 expression and function and will discuss targeting Mcl-1 as a potential therapeutic strategy to enhance the resolution of inflammation through accelerating neutrophil apoptosis.
Highlights
Neutrophils or polymorphonuclear leukocytes are the most abundant cells of the innate immune system and form the first line of defence against invading pathogens
Mcl-1 has some unusual properties compared with other Bcl-2 family members, including an extremely high turnover rate [18, 19], which is well suited for dynamic control of neutrophil survival
Neutrophil death is tightly regulated on a constitutive basis, and the complexity increases under pathological conditions, so that it is often difficult to decide whether survival or apoptosis is most favourable from the host’s perspective
Summary
Neutrophils or polymorphonuclear leukocytes are the most abundant cells of the innate immune system and form the first line of defence against invading pathogens. Neutrophil survival/apoptosis emerged as one of the control points in resolving inflammation. Neutrophil apoptosis is tightly regulated by a complex network of signalling pathways that controls expression and degradation of key molecules, including Bcl-2 family proteins, activation of MAP kinases, NF-κB, and caspases [1, 3, 4]. Mcl-1 has some unusual properties compared with other Bcl-2 family members, including an extremely high turnover rate [18, 19], which is well suited for dynamic control of neutrophil survival. Understanding the molecular mechanisms that control Mcl-1 turnover and function may provide a rational basis for development of novel therapeutic approaches to modulate neutrophil apoptosis and to facilitate resolution of neutrophil-mediated inflammatory diseases
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