Modulating neutrophil apoptosis

Abstract

Polymorphonuclear neutrophils are short-lived phagocytic cells that serve as cardinal early cellular effectors of innate immunity. Both oxidative and non-oxidative mechanisms contribute to microbial killing by the neutrophil. Neutrophil defence mechanisms are potent but non-specific, with the result that inadvertent injury to host tissues commonly accompanies the activation of a neutrophil mediated response; this bystander injury has been implicated in the tissue injury of sepsis. The capacity for neutrophils to cause injury to host tissues is attenuated by the relatively short in vivo lifespan of the neutrophil, a consequence of a constitutively expressed program of apoptosis. That program can be inhibited, and neutrophil survival prolonged, through the interaction of the neutrophil with a variety of mediators of both microbial and host origin. These, in turn, inhibit apoptosis by increasing the expression of anti-apoptotic genes within the neutrophil: interleukin (IL)1beta and a novel cytokine-like molecule pre-B cell colony-enhancing factor (PBEF) are central to this inhibitory influence. Conversely, the phagocytosis of a micro-organism activates the apoptotic program, and so contributes to the resolution of acute inflammation. A complex series of interactions between the neutrophil and microorganisms or their products regulates the duration and intensity of an inflammatory response, and so provides an attractive target for therapeutic manipulation.