The clinical consequences of neutrophil priming.

PURPOSE OF REVIEW: Neutrophils priming has been long studied in vitro. Recent studies describe it in vivo. In pathophysiological conditions, complex, heterogeneous characteristics of priming are described in the last few years. RECENT FINDINGS: Priming can occur systemically when insults such as sepsis or trauma result in an array of circulating mediators and circulating primed neutrophils seem to exert detrimental effects either directly, or indirectly by interacting with other cells, thereby contributing to the development of organ dysfunction. Local priming of neutrophils augments their ability to clear infection, but may also lead to local bystander tissue injury, for example, in the inflamed joint. The complexity, heterogeneity and dynamic nature of inflammatory responses and the accessibility of cells from local sites make neutrophil priming challenging to study in human disease; however, recent advances have made significant progress to this field. SUMMARY: Herein, we summarize the literature regarding neutrophil priming in selected conditions. In some diseases and in the setting of specific genetic influences, the priming repertoire seems to be restricted, with only some neutrophil functions upregulated. A greater understanding of the nature of neutrophil priming and its role in human disease is required before this process becomes tractable to therapeutic intervention.

Priming and de-priming of neutrophil responses in vitro and in vivo.

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.

Differential activities of the Drosophila JAK/STAT pathway ligands Upd, Upd2 and Upd3.

JAK/STAT signalling in vertebrates is activated by multiple cytokines and growth factors. By contrast, the Drosophila genome encodes for only three related JAK/STAT ligands, Upd, Upd2 and Upd3. Identifying the differences between these three ligands will ultimately lead to a greater understanding of this disease-related signalling pathway and its roles in development. Here, we describe the analysis of the least well characterised of the Upd-like ligands, Upd3. We show that in tissue culture-based assays Upd3-GFP is secreted from cells and appears to interact with the extracellular matrix (ECM) in a similar manner to Upd, while still non-autonomously activating JAK/STAT signalling. Quantification of each of the Upd-like ligands in conditioned media has allowed us to determine the activity of equal amounts of each ligand on JAK/STAT ex vivo and reveals that Upd is the most potent ligand in this system. Finally, investigations into the effects of ectopic expression of Upd3 in vivo have confirmed its ability to activate pathway signalling at long-distance.