Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice release_wgh25pzi6rgk5kigj6kd463sbm

by Karen A Fortner, Luz Blanco, Iwona Buskiewicz, Nick Huang, Pamela C Gibson, Deborah L Cook, Hege L Pedersen, Peter S T Yuen, Michael Murphy, Andreas Perl, Mariana Kaplan, Ralph Budd

Published in Lupus Science and Medicine by BMJ.

2020   Volume 7, Issue 1, e000387

Abstract

<jats:sec><jats:title>Objectives</jats:title>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.</jats:sec><jats:sec><jats:title>Methods</jats:title>Lupus-prone MRL-<jats:italic>lpr</jats:italic> 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.</jats:sec><jats:sec><jats:title>Results</jats:title>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 .</jats:sec><jats:sec><jats:title>Conclusions</jats:title>These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.</jats:sec>
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Date   2020-04-16
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