Armed for destruction: formation, function and trafficking of neutrophil granules

Abstract

Neutrophils respond nearly instantly to infection, rapidly deploying a potent enzymatic and chemical arsenal immediately upon entering an infected site. This capacity for rapid and potent responses is endowed by stores of antimicrobial proteins contained in readily mobilizable granules. These granules contain the proteins necessary to mediate the recruitment, chemotaxis, antimicrobial function and NET formation of neutrophils. Four granule types exist, and are sequentially deployed as neutrophils enter infected sites. Secretory vesicles are released first, enabling recruitment of neutrophils out of the blood. Next, specific and gelatinase granules are released to enable neutrophil migration and begin the formation of an antimicrobial environment. Finally, azurophilic granules release potent antimicrobial proteins at the site of infection and into phagosomes. The step-wise mobilization of these granules is regulated by calcium signaling, while specific trafficking regulators and membrane fusion complexes ensure the delivery of granules to the correct subcellular site. In this review, we describe neutrophil granules from their formation through to their deployment at the site of infection, focusing on recent developments in our understanding of the signaling pathways and vesicular trafficking mechanisms which mediate neutrophil degranulation.

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Fig. 1
Fig. 2

Abbreviations

AP:

Adaptor protein

CHS:

Chédiak–Higashi syndrome

CR3:

Complement receptor 3

DAG:

Diacylglycerol

DOCK2:

Dedicator of cytokinesis protein 2

ER:

Endoplasmic reticulum

FcR:

Fc receptor

fMLF:

N-formylmethionyl-leucyl-phenylalanine

GAP:

GTPase activating protein

GEF:

Guanine exchange factor

GPCR:

G protein-coupled receptor

IP3 :

Inositol-3-phosphate

ITAM:

Immunoreceptor tyrosine-based activation motif

MPO:

Myeloperoxidase

NET:

Neutrophil extracellular trap

PA:

Phosphatidic acid

PI3K:

Phosphatidyleinositiol-3-kinase

SFK:

Src-family kinase

SGD:

Specific granule deficiency

SNAP:

Synaptosomal-associated protein

SOC:

Store-operated channel

SV:

Secretory vesicle

VAMP:

Vesicle-associated membrane protein.

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Acknowledgements

The work in B.H.’s laboratory is supported by an operating grant from the Canadian Institutes for Health Research (MOP-123419), discovery grant #418194 from the Natural Sciences and Engineering Council of Canada, and an Ontario Ministry of Research and Innovation Early Researcher Award. C.Y. is a Vanier Scholar and holds a Canadian Institutes for Health Research MD/PhD Studentship.

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Yin, C., Heit, B. Armed for destruction: formation, function and trafficking of neutrophil granules. Cell Tissue Res 371, 455–471 (2018). https://doi.org/10.1007/s00441-017-2731-8

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Keywords

  • Neutrophil
  • Degranulation
  • Granulopoiesis
  • Calcium
  • GTPase
  • Vesicular traffic