Priming and de‐priming of neutrophil responses in vitro and in vivo

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.

Real-time deformability cytometry reveals sequential contraction and expansion during neutrophil priming

“…As the first responders to infection, neutrophils require highly tuned functional flexibility. The ability to change functional status in response to immune‐modulators allows the neutrophil to patrol the body in a relatively quiescent state while remaining capable of sensing and then employing appropriate responses when threats arise . When quiescent or un‐primed neutrophils are exposed to certain proinflammatory cytokines or chemokines (e.g., TNF, fMLF, platelet‐activating factor [PAF], and GM‐CSF), they transition into a primed state.…”

“…The ability to change functional status in response to immune-modulators allows the neutrophil to patrol the body in a relatively quiescent state while remaining capable of sensing and then employing appropriate responses when threats arise. 1 When quiescent or un-primed neutrophils are exposed to certain proinflammatory cytokines or chemokines (e.g., TNF, fMLF, platelet-activating factor In addition to the described functional and biochemical changes, neutrophils undergoing activation exhibit morpho-rheological (MORE) changes to their biophysical shape. It has been reported that activated neutrophils are smaller and stiffer than their unactivated and un-primed counterparts, [10][11][12][13] although there exist conflicting reports of neutrophils expanding poststimulation.…”

MicroRNA‐223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes

“…In addition, neutrophil–hepatic stellate cell (HSC) interactions may drive the progression of liver fibrosis in experimental steatohepatitis . Emerging evidence suggests that neutrophil activation and functions are regulated by many proinflammatory mediators, cytokines, growth factors, transcription factors, and epigenetic factors (e.g., microRNAs [miRNAs]) . Among miRNAs, microRNA‐223 (miR‐223) is expressed at the highest levels in neutrophils, playing a critical role in attenuating neutrophil maturation and activation .…”

Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex

“…Our earlier studies have demonstrated that such secretory organelles containing CD11b, FPR1and, FPR2 are mobilized to the neutrophil surface by priming agents such as TNFα and LPS [65][66][67]. Considering the high levels of TNFα in a number of inflammatory diseases such as rheumatoid arthritis, suggests that the mechanism underlying the neutrophil priming process and its consequences both in vitro and in vivo may offer new opportunities for therapeutic intervention in pathological settings [68]. Despite the robust release of ROS induced by low nM concentrations of RE, much higher concentrations were needed to induce neutrophil chemotaxis.…”