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

• Published in: Lupus science & medicine Vol. 7; no. 1; p. e000387
• Main 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, Andras, Kaplan, Mariana J, Budd, Ralph C
• Format: Journal Article
• Language: English
• Published: England Lupus Foundation of America 16.04.2020; BMJ Publishing Group LTD; BMJ Publishing Group
• Series: Original research
• Subjects: Animal Models; Animals; Antiviral drugs; Autoantibodies - metabolism; autoimmune diseases; Disease Models, Animal; Drinking water; Extracellular Traps - immunology; Female; Flow cytometry; Humans; Immunoglobulins; inflammation; Interferon Type I - immunology; Kidney - metabolism; Kidney - physiopathology; Kidney Diseases - metabolism; Kidney Diseases - physiopathology; Kidneys; Laboratory animals; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - physiopathology; Lymphatic system; Lymphocytes; Male; Medical disciplines: 700; Medisinske Fag: 700; Metabolism; Mice; Mice, Inbred MRL lpr; Microscopy; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Neutrophils; Neutrophils - immunology; Organophosphorus Compounds - pharmacology; Oxidation-Reduction - drug effects; Oxidative stress; Oxidative Stress - immunology; Proteins; Reactive Oxygen Species - metabolism; systemic lupus erythematosus; T cells; T-Lymphocytes - immunology; Ubiquinone - analogs & derivatives; Ubiquinone - pharmacology; VDP; Oregon; California; United States > US; Texas; Pennsylvania; autoimmune diseases; systemic lupus erythematosus; T cells; inflammation
• ISSN: 2053-8790; 2053-8790
• DOI: 10.1136/lupus-2020-000387

ObjectivesRecent 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.MethodsLupus-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.ResultsMitoQ-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 .ConclusionsThese findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.