Katja L. Vogt

People with activated PI3 kinase delta syndrome 1 (APDS1) suffer from immune deficiency and severe bronchiectasis. APDS1 is caused by dominant activating mutations of the PIK3CD gene that encodes the PI3 kinase delta (PI3Kδ) catalytic subunit. Despite the importance of innate immunity defects in bronchiectasis, there has been limited investigation of neutrophils or macrophages in APDS1 patients or mouse models. Zebrafish embryos provide an ideal system to study neutrophils and macrophages. We used CRISPR-Cas9 and CRISPR-Cpf1, with oligonucleotide-directed homologous repair, to engineer zebrafish equivalents of the two most prevalent human APDS1 disease mutations. These zebrafish pik3cd alleles dominantly caused excessive neutrophilic inflammation in a tail-fin injury model. They also resulted in total body neutrophilia in the absence of any inflammatory stimulus but normal numbers of macrophages. Exposure of zebrafish to the PI3Kδ inhibitor CAL-101 reversed the total body neutrophilia. There was no apparent defect in neutrophil maturation or migration, and tail-fin regeneration was unimpaired. Overall, the finding is of enhanced granulopoeisis, in the absence of notable phenotypic change in neutrophils and macrophages.

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.

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 are 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.