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Published on: July 28, 2016
Myeloperoxidase Modulates Hydrogen Peroxide Mediated Cellular Damage in Murine Macrophages
Chaorui Guo1, Inga Sileikaite1, Michael J Davies1
1Department of Biomedical Sciences, University of Copenhagen, Panum, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark.
Abstract:
Myeloperoxidase (MPO) is involved in the development of many chronic inflammatory diseases, in addition to its key role in innate immune defenses. This is attributed to the excessive production of hypochlorous acid (HOCl) by MPO at inflammatory sites, which causes tissue damage. This has sparked wide interest in the development of therapeutic approaches to prevent HOCl-induced cellular damage including supplementation with thiocyanate (SCN-) as an alternative substrate for MPO. In this study, we used an enzymatic system composed of glucose oxidase (GO), glucose, and MPO in the absence and presence of SCN-, to investigate the effects of generating a continuous flux of oxidants on macrophage cell function. Our studies show the generation of hydrogen peroxide (H2O2) by glucose and GO results in a dose- and time-dependent decrease in metabolic activity and cell viability, and the activation of stress-related signaling pathways. Interestingly, these damaging effects were attenuated by the addition of MPO to form HOCl. Supplementation with SCN-, which favors the formation of hypothiocyanous acid, could reverse this effect. Addition of MPO also resulted in upregulation of the antioxidant gene, NAD(P)H:quinone acceptor oxidoreductase 1. This study provides new insights into the role of MPO in the modulation of macrophage function, which may be relevant to inflammatory pathologies.
Insights
Myeloperoxidase (MPO) generates damaging oxidants, but thiocyanate (SCN-) supplementation can mitigate these effects on macrophage function, offering therapeutic potential for inflammatory diseases.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Myeloperoxidase (MPO) plays a dual role in innate immunity and chronic inflammatory diseases.
- Excessive MPO-derived hypochlorous acid (HOCl) production at inflammatory sites causes significant tissue damage.
- Thiocyanate (SCN-) is explored as a therapeutic agent due to its potential to act as an alternative MPO substrate.
Purpose of the Study:
- To investigate the impact of sustained oxidant generation on macrophage function.
- To evaluate the protective effects of MPO and SCN- against oxidant-induced cellular damage.
- To explore the role of MPO in modulating macrophage-related signaling pathways.
Main Methods:
- Utilized an enzymatic system with glucose oxidase (GO), glucose, and MPO.
- Assessed macrophage metabolic activity, cell viability, and stress-related signaling.
- Quantified the effects of HOCl and hypothiocyanous acid (HOCl) on macrophage function.
- Analyzed the expression of antioxidant genes, including NAD(P)H:quinone acceptor oxidoreductase 1.
Main Results:
- Hydrogen peroxide (H2O2) from glucose/GO decreased macrophage metabolic activity and viability.
- MPO addition attenuated H2O2-induced damage by forming HOCl.
- SCN- supplementation reversed the damaging effects, favoring hypothiocyanous acid formation.
- MPO upregulated the antioxidant gene NAD(P)H:quinone acceptor oxidoreductase 1.
Conclusions:
- Sustained oxidant generation negatively impacts macrophage function.
- MPO and SCN- can modulate MPO activity to protect macrophages from oxidative stress.
- These findings offer insights into MPO's role in inflammation and potential therapeutic strategies.
