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Regulatory Mechanisms in Neutrophil Degranulation

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Immunopharmacology and Inflammation

Abstract

Bone marrow-derived circulating neutrophils of the innate immune system extravasate through blood vessel walls to sites of infection and injury where they orchestrate a myriad of protective and destructive host responses during acute inflammation. Although neutrophils comprise the first line of defense against exogenous and endogenous insults, these abundantly produced white blood cells can damage tissues and consequently increase the severity of inflammatory diseases. Neutrophils undergo receptor-mediated respiratory burst and release inflammatory mediators by degranulation of membrane-bound secretory granules after migrating from the bloodstream in response to chemotactic signals generated at inflammatory foci. Many studies point to degranulation as the chief causative process involved in inflammatory disorders, but the underlying mechanisms remain poorly understood. We discuss the complex interplay of distal, intracellular pathways involving numerous signaling proteins that are implicated in the exocytosis of granular contents. This review summarizes current knowledge of neutrophil biology and highlights mechanisms that regulate degranulation.

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Abbreviations

a2V:

V-ATPase subunit

ATP:

Adenosine triphosphate

ATPase:

Adenosine triphosphatase

BoNT:

Botulinum neurotoxin

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

fMLP:

N-formyl-methionyl-leucyl-phenylalanine

GDP:

Guanosine diphosphate

GEF:

Guanine nucleotide exchange factor

GPCR:

G protein-coupled receptor

GTP:

Guanosine triphosphate

GTPase:

Guanosine triphosphatase

GTPγS:

Guanosine 5′-O-(γ-thio) triphosphate

IL-8:

Interleukin-8

LTF:

Lactoferrin

MAP:

Mitogen-activated protein

MARCKS:

Myristoylated alanine-rich C kinase substrate

MMP:

Matrix metalloprotease

MPO:

Myeloperoxidase

NADPH:

Nicotinamide adenine dinucleotide phosphate

NET:

Neutrophil extracellular trap

Nexinhibs:

Neutrophil exocytosis inhibitors

NSF:

N-ethylmaleimide-sensitive factor

PI3K:

Phosphatidylinositol 3-kinase

PIKfyve:

FYVE domain-containing phosphatidylinositol 3-phosphate 5-kinase

PIP2 :

Phosphatidylinositol 4,5-bisphosphate

PMA:

Phorbol 12-myristate 13-acetate

PTP-MEG2:

Protein tyrosine phosphatase MEG2

Q-SNARE:

SNARE expressing a key glutamine residue in the SNARE-binding domain; also known as t-SNARE in exocytosis; members include syntaxins, SNAP-23, and SNAP-25

Rac:

ras-related C3 botulinum toxin substrate

ROS:

Reactive oxygen species

R-SNARE:

SNARE expressing a key arginine residue in the SNARE-binding domain; also known as v-SNARE in exocytosis; members include VAMPs

SFKs:

src family of non-receptor tyrosine kinases

SNAP:

N-ethylmaleimide-sensitive factor attachment protein or synaptosomal-associated protein

SNARE:

N-ethylmaleimide-sensitive factor attachment protein receptor

SV:

Secretory vesicle N-ethylmaleimide-sensitive factor attachment protein receptor

TeNT:

Tetanus neurotoxin

TLR:

Toll-like receptor

VAMP:

Vesicle-associated membrane protein

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  1. Alberta Respiratory Centre (ARC) Research, Department of Medicine, University of Alberta, Edmonton, AB, Canada

    Lindsey C. Felix, Sarah Almas & Paige Lacy

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  1. Lindsey C. Felix
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  2. Sarah Almas
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  1. Department of Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy

    Carlo Riccardi

  2. Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Francesca Levi-Schaffer

  3. Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Ekaterini Tiligada

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Felix, L.C., Almas, S., Lacy, P. (2018). Regulatory Mechanisms in Neutrophil Degranulation. In: Riccardi, C., Levi-Schaffer, F., Tiligada, E. (eds) Immunopharmacology and Inflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-77658-3_8

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