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Review
. 2020 Feb 11;21(4):1183.
doi: 10.3390/ijms21041183.

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

Katharine M Lodge  1 , Andrew S Cowburn  1 , Wei Li  2 , Alison M Condliffe  3
Affiliations
Review

The Impact of Hypoxia on Neutrophil Degranulation and Consequences for the Host

Katharine M Lodge et al. Int J Mol Sci. .

Abstract

Neutrophils are key effector cells of innate immunity, rapidly recruited to defend the host against invading pathogens. Neutrophils may kill pathogens intracellularly, following phagocytosis, or extracellularly, by degranulation and the release of neutrophil extracellular traps; all of these microbicidal strategies require the deployment of cytotoxic proteins and proteases, packaged during neutrophil development within cytoplasmic granules. Neutrophils operate in infected and inflamed tissues, which can be profoundly hypoxic. Neutrophilic infiltration of hypoxic tissues characterises a myriad of acute and chronic infectious and inflammatory diseases, and as well as potentially protecting the host from pathogens, neutrophil granule products have been implicated in causing collateral tissue damage in these scenarios. This review discusses the evidence for the enhanced secretion of destructive neutrophil granule contents observed in hypoxic environments and the potential mechanisms for this heightened granule exocytosis, highlighting implications for the host. Understanding the dichotomy of the beneficial and detrimental consequences of neutrophil degranulation in hypoxic environments is crucial to inform potential neutrophil-directed therapeutics in order to limit persistent, excessive, or inappropriate inflammation.

Keywords: degranulation; hypoxia; neutrophils.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of hypoxia-enhanced neutrophil degranulation. Hypoxia increases neutrophil degranulation in a phosphoinositide 3-kinase γ (PI3Kγ)-dependent manner: activation of PI3Kγ by the G protein-coupled receptor βγ (G βγ) subunit induces the production of PIP3 by phosphorylation of PIP2. PIP3 signals via the AKT cascade and activates Rac2, which controls actin assembly. Hypoxia also induces the formation of focal “actin caps”. This rearrangement of the actin cytoskeleton likely facilitates granule translocation and fusion with the plasma membrane. Hypoxia and PI3K signalling increase autophagy, which enhances degranulation. Hypoxia and autophagy reduce reactive oxygen species (ROS) via lack of molecular oxygen and mitophagy, respectively; lack of ROS increases degranulation. Hypoxia stabilises hypoxia inducible factor (HIF)α, which dimerises with HIFβ in the nucleus. HIF heterodimer signalling increases the synthesis of granule proteins and may increase neutrophil extracellular trap (NET) production, which is predominantly ROS-dependent. Dashed lines indicate where pathways are uncertain or unknown.
Figure 2
Figure 2
Consequences of hypoxia-enhanced neutrophil degranulation. Hypoxia increases the degranulation of azurophil, specific and gelatinase granules from neutrophils, which releases granule contents (e.g., neutrophil elastase (NE), myeloperoxidase (MPO), lactoferrin, and matrix metalloproteinase 9 (MMP-9)) into the extracellular space. Augmented release of these proteins and proteases may have beneficial effects: improved access to areas of infection through the extracellular matrix (double-headed arrow) and increased pathogen killing (damage indicated by lightning strike), or detrimental effects: host tissue damage, tumour growth and metastasis (double-headed arrow), and perpetuation of inflammation.
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