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.
- autoimmune diseases
- systemic lupus erythematosus
- T cells
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KAF and LPB contributed equally.
Contributors KAF performed all animal breeding, administration of MitoQ, organ harvest, purification of lymphocyte subsets and flow cytometry, serum creatinine and BUN, and urine albumin/creatinine. LPB performed the ROS and NET formation assays, and immune complex staining of kidneys. IB performed the assays for MAVS oligomerisation. NK and AP performed the autoantibody ELISAs. PCG and DLC performed histological analyses. PSTY performed the serum creatinine analysis. MPM provided the MitoQ and advised on mitochondrial studies. MPM and RCB directed the work.
Funding This work was supported by National Institutes of Health grants AI119979 and GM118228 (to RCB), AI048079, AI072648 and AI122176 (to AP), the Central New York Community Foundation (to AP), the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z) (to MPM), and the Intramural Research Program at NIAMS (ZIAAR041199). MitoQ was kindly provided by MitoQ, Auckland, New Zealand.
Competing interests MPM helped develop MitoQ and has a commercial interest in MitoQ.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. For inquiries, please contact the corresponding author RCB at email@example.com.
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