Abstract
The innate immune system displays heterologous memory characteristics, which are characterized by stronger responses to a secondary challenge. This phenomenon termed trained immunity relies on epigenetic and metabolic rewiring of innate immune cells. As reactive oxygen species (ROS) production has been associated with the trained immunity phenotype, we hypothesized that the increased ROS levels and the main intracellular redox molecule glutathione play a role in the induction of trained immunity. Here we show that pharmacological inhibition of ROS in an in vitro model of trained immunity did not influence cell responsiveness; the modulation of glutathione levels reduced pro-inflammatory cytokine production in human monocytes. Single nucleotide polymorphisms (SNPs) in genes involved in glutathione metabolism were found to be associated with changes in pro-inflammatory cytokine production capacity upon trained immunity. Also, plasma glutathione concentrations were positively associated with ex vivo IL-1β production, a biomarker of trained immunity, produced by monocytes of BCG-vaccinated individuals. In conclusion, glutathione metabolism is involved in the induction of trained immunity, and future studies are warranted to explore its functional consequences in human diseases.
Highlights
Until recently, adaptive immunity was thought to be the only component of host defense characterized by the capacity to retain memory, tailoring T and B cell responses to a specific antigen
We tested if common Single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) > 0.05 in genes relevant for glutathione metabolism were associated to changes in pro-inflammatory cytokine production capacity of monocytes upon β-glucan and Bacillus Calmette-Guérin (BCG)
Trained macrophages rely on a high energy metabolism, with increased glycolysis, TCA cycle, and oxidative phosphorylation, to mount a response with enhanced pro-inflammatory cytokine production [6,22]
Summary
Adaptive immunity was thought to be the only component of host defense characterized by the capacity to retain memory, tailoring T and B cell responses to a specific antigen. Trained immunity is rooted in epigenetic changes that modulate the accessibility of genes of the pro-inflammatory response for the transcriptional machinery of the cell. Epigenetic rewiring in trained innate immune cells is accompanied by metabolic changes that promote pathways such as glycolysis, oxidative phosphorylation, and the cholesterol biosynthesis [5,6]. Metabolites derived from these pathways are signaling molecules and cofactors that can in turn modulate the activity of chromatin modifying enzymes. Stimuli that induce trained immunity, such BCG and oxLDL, increase the production of reactive oxygen species (ROS). GSH, which in turn would influence the strength of trained immunity responses
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