Abstract
The activation status of neutrophils can cycle from basal through primed to fully activated ("green-amber-red"), and at least in vitro, primed cells can spontaneously revert to a near basal phenotype. This broad range of neutrophil responsiveness confers extensive functional flexibility, allowing neutrophils to respond rapidly and appropriately to varied and evolving threats throughout the body. Primed and activated cells display dramatically enhanced bactericidal capacity (including augmented respiratory burst activity, degranulation and longevity), but this enhancement also confers the capacity for significant unintended tissue injury. Neutrophil priming and its consequences have been associated with adverse outcomes in a range of disease states, hence understanding the signalling processes that regulate the transition between basal and primed states (and back again) may offer new opportunities for therapeutic intervention in pathological settings. A wide array of host- and pathogen-derived molecules is able to modulate the functional status of these versatile cells. Reflecting this extensive repertoire of potential mediators, priming can be established by a range of signalling pathways (including mitogen-activated protein kinases, phosphoinositide 3-kinases, phospholipase D and calcium transients) and intracellular processes (including endocytosis, vesicle trafficking and the engagement of adhesion molecules). The signalling pathways engaged, and the exact cellular phenotype that results, vary according to the priming agent(s) to which the neutrophil is exposed and the precise environmental context. Herein we describe the signals that establish priming (in particular for enhanced respiratory burst, degranulation and prolonged lifespan) and describe the recently recognised process of de-priming, correlating in vitro observations with in vivo significance.
Highlights
Circulating neutrophils are quiescent, and in health the vast majority undergo final disposal without encountering an activating signal
Neutrophils that have been exposed to a range of agonists enter a state of high alert, with the capacity to respond aggressively if a further activating stimulus is encountered
We have previously shown that phosphoinositide 3‐kinases (PI3Ks)‐dependent PtdIns (3,4,5)P3 (PIP3) generation correlates with reactive oxygen species (ROS) release in vitro, and TNF‐primed fMLF‐stimulated human neutrophils display biphasic PI3K activation, with the second (PI3Kδ isoform‐dependent) phase governing primed ROS generation.[32]
Summary
Circulating neutrophils are quiescent, and in health the vast majority undergo final disposal without encountering an activating signal. Neutrophils that have been exposed to a range of agonists enter a state of high alert, with the capacity to respond aggressively (eg, through degranulation, respiratory burst activity and increased lifespan) if a further activating stimulus is encountered This pre‐activation or primed state was first recognised in vitro,[1] and shortly afterwards shown to occur in vivo in the setting of systemic infection.[2] A wide variety of priming agents (chemokines, cytokines, alarmins, integrins, pathogen‐ derived molecules and mechanical forces) have been identified, and primed neutrophils circulate in vivo in many inflammatory diseases (eg, rheumatoid arthritis[3] and cystic fibrosis4) and pathological states (eg, trauma or cardiopulmonary bypass[5,6]). We describe the signals that establish priming and describe how neutrophils can de‐prime, correlating in vitro observations with in vivo significance
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