Hypoxia Modulates the Response of Mast Cells to Staphylococcus aureus Infection

Abstract

To study the antimicrobial function of immune cells ex vivo, cells are commonly cultivated under atmospheric oxygen concentrations (20–21%; normoxia), although the physiological oxygen conditions in vivo are significantly lower in most tissues. Especially during an acute infection, oxygen concentration locally decreases to hypoxic levels around or below 1%. The goal of this study was to investigate the effect of hypoxia on the activity of mast cells (MCs). MCs were cultivated for 3 or 24 h at 1% O2 in a hypoxia glove box and co-incubated with heat-inactivated Staphylococcus aureus. When incubating the cells for 24 h under hypoxia, the transcriptional regulator hypoxia-inducible factor 1α (HIF-1α) was stabilized and resulted in increased extracellular trap formation and decreased phagocytosis. Interestingly, while phagocytosis of fluorescent S. aureus bioparticles as well as the release of extracellular traps remained unaffected at 3 h hypoxia, the secretion of the prestored mediator histamine was increased under hypoxia alone. In contrast, the release of TNF-α was generally reduced at 3 h hypoxia. Microarray transcriptome analysis revealed 13 genes that were significantly downregulated in MCs comparing 3 h hypoxia versus normoxia. One interesting candidate is sec24, a member of the pre-budding complex of coat protein complex II (COPII), which is responsible for the anterograde transport of proteins from the ER to the Golgi apparatus. These data lead to the suggestion that de novo synthesized proteins including crucial factors, which are involved in the response to an acute infection like TNF-α, may eventually be retained in the ER under hypoxia. Importantly, the expression of HIF-1α was not altered at 3 h. Thus, our data exhibit a HIF-1α-independent reaction of MCs to short-term hypoxia. We hypothesize that MCs respond to short-term low oxygen levels in a HIF-1α-independent manner by downregulating the release of proinflammatory cytokines like TNF-α, thereby avoiding uncontrolled degranulation, which could lead to excessive inflammation and severe tissue damage.

iTRAQ‐based proteomic and bioinformatic characterization of human mast cells upon infection by the influenza A virus strains H1N1 and H5N1

“…Accumulating data have indicated that HIF‐1a affects degranulation and the expression of inflammatory factors in MCs . A recent study demonstrated that HIF‐1a could contribute to the response to Staphylococcus aureus infection in MCs under hypoxia . In the present study, the HIF‐1a signaling pathway was also significantly modulated by DEPs in H5N1 virus‐infected HMCs.…”

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

“…McGovern et al and Hoenderdos et al found that this hypoxia-augmented degranulation occurred rapidly (within 2 h), was not prevented by inhibition of protein translation, and could not be recapitulated by pharmacological HIF-1α stabilisation [24,32]. Together these data suggest that hypoxia drives an early increase in the release of pre-formed proteins and proteases in a manner that can be partially or totally HIF-independent, analogous to the increased release of histamine from mast cells [65] and WPBs from endothelial cells [75], but in contrast to IL-8 release from macrophages, which was HIF-independent but reliant on new protein synthesis [70]. Of interest, variable responses to different agonists have been seen in neutrophils, with both PAF and GM-CSF, but not TNF-α, able to promote hypoxic degranulation [24].…”

“…Hypoxia has been shown to modulate protein secretion from several cell types, including immune cells and endothelial cells. Steiner et al showed that rats exposed to systemic hypoxia experienced a rapid (within minutes) and sustained increase in mast cell degranulation in vivo [64], and the hypoxic culture of mast cells demonstrated a HIF-independent increase in release of pre-stored histamine assessed at 3 h [65]. Conversely, TNF-α secretion was decreased, and transcriptomic analysis revealed the downregulation of Sec24A, which is implicated in cytokine transport from the endoplasmic reticulum to the Golgi.…”

<b><i>Staphylococcus aureus</i></b> and Host Immunity in Recurrent Furunculosis

“…Mast cells also play an important protective role against various microbial infections, like S. aureus , by phagocytosis and by releasing mediators (e. g. tumor necrosis factor-α and histamine) [45]. However, it was proven that in the S. aureus -infected mice, severe infiltration of inflammatory cells in the dermis was observed, and mast cells were markedly accumulated in the skins.…”