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

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.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

“…Information on the effect of hypoxia on NETosis is controversial. From the one hand, knockout of Hif-1α (the main transcription factor regulating adaptation to hypoxia) suppressed NETosis, while pharmacological stabilization of Hif-1α stimulated it [ 57 ]. On the other hand, NETosis induced by PMA (but not S. aureus ) decreased with hypoxia, and this effect was not dependent on Hif-1α [ 58 ].…”

If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

“…HIF‐1α stabilisation increases the lifespan of neutrophils and their bactericidal capabilities in multiple experimental models [11,12]. Neutrophil degranulation is an important process in pathogen control, but can cause extensive tissue damage when uncontrolled in chronic inflammatory diseases where tissue hypoxia is often a hallmark [13]. Human neutrophils in hypoxia have augmented degranulation, while neutrophils with stabilised HIF‐α, after treatment with the pan hydroxylase inhibitor, dimethyloxalylglycine (DMOG), interestingly do not have the same increased degranulation [14].…”

HIF2α is a direct regulator of neutrophil motility

“…When oxygen levels decrease, PHDs get inactivated, which results in HIFα stabilization and transcription of relevant target genes. Interestingly, HIF1α-deficiency results in subdued inflammation 2,3 while, inversely, PHD inactivation and/or HIFα stabilization leads to enhanced neutrophil survival, 4,10 chemotaxis and degranulation (reviewed in 11 ). Although both HIFα subunits have overlapping activities, unique roles for HIF2α, including in neutrophil function, have been reported.…”