Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lprmice
Open Access
- 16 April 2020
- journal article
- research article
- Published by BMJ in Lupus Science & Medicine®
- Vol. 7 (1), e000387
- https://doi.org/10.1136/lupus-2020-000387
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.Keywords
Funding Information
- Wellcome Trust (110159/Z/15/Z)
- National Institute of Allergy and Infectious Diseases (AI048079, AI072648, AI119979, AI122176)
- Central New York Community Foundation
- National Institute of General Medical Sciences (GM118228)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (ZIAAR041199)
- Medical Research Council (MC_U105663142)
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