Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice.

Abstract

OBJECTIVES:

Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.

METHODS:

Lupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.

RESULTS:

MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .

CONCLUSIONS:

These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

• Authors: Karen A Fortner, Luz P Blanco, Iwona Buskiewicz, Nick Huang, Pamela C Gibson, Deborah L Cook, Hege L Pedersen, Peter S T Yuen, Michael P Murphy, Andras Perl, Mariana J Kaplan, Ralph C Budd
• Journal: Lupus science & medicine (Lupus Sci Med) Vol. 7 Issue 1 (04 2020) ISSN: 2053-8790 [Print] England
• PMID: 32343673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Autoantibodies
• Interferon Type I
• Organophosphorus Compounds
• Reactive Oxygen Species
• Ubiquinone
• mitoquinone

Topics

• Animals
• Autoantibodies (metabolism)
• Disease Models, Animal
• Extracellular Traps (immunology)
• Female
• Humans
• Interferon Type I (immunology)
• Kidney (metabolism, physiopathology)
• Kidney Diseases (metabolism, physiopathology)
• Lupus Erythematosus, Systemic (immunology, physiopathology)
• Male
• Mice
• Mice, Inbred MRL lpr
• Mitochondria (metabolism)
• Neutrophils (immunology)
• Organophosphorus Compounds (pharmacology)
• Oxidation-Reduction (drug effects)
• Oxidative Stress (immunology)
• Reactive Oxygen Species (metabolism)
• T-Lymphocytes (immunology)
• Ubiquinone (analogs & derivatives, pharmacology)