Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice. Issue 1 (16th April 2020)

• Record Type: Journal Article
• Authors: Fortner, Karen A; Blanco, Luz P; Buskiewicz, Iwona; Huang, Nick; Gibson, Pamela C; Cook, Deborah L; Pedersen, Hege L; Yuen, Peter S T; Murphy, Michael P; Perl, Andreas; Kaplan, Mariana J; Budd, Ralph C
• Is Part Of: Lupus science & medicine. Volume 7:Issue 1(2020)
• Publication Date: 2020-04-16
• Subjects: autoimmune diseases -- systemic lupus erythematosus -- T cells -- inflammation; Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1136/lupus-2020-000387
• Languages: English
• ISSNs: 2398-8851

Abstract

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.