Article Text

Download PDFPDF

Original research
Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice
  1. Karen A Fortner1,
  2. Luz P Blanco2,
  3. Iwona Buskiewicz3,
  4. Nick Huang4,
  5. Pamela C Gibson5,
  6. Deborah L Cook5,
  7. Hege L Pedersen2,
  8. Peter S T Yuen6,
  9. Michael P Murphy7,8,
  10. Andras Perl4,
  11. Mariana J Kaplan2 and
  12. Ralph C Budd1
  1. 1Vermont Center for Immunology and Infectious Diseases, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA
  2. 2Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (NIH), Bethesda, MD, USA
  3. 3Department of Microbiology and Immunology, Upstate Medical University, Syracuse, NY, New York
  4. 4Rheumatology Clinic, Upstate University Hospital, Syracuse, NY, New York
  5. 5Department of Pathology and Laboratory Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA
  6. 6Renal Diagnostics and Therapeutic Unit, Kidney Diseases Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  7. 7MRC Mitochondrial Biology Unit, Biomedical Campus, University of Cambridge, Cambridge, CB2 0XY, UK
  8. 8Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
  1. Correspondence to Dr Ralph C Budd; ralph.budd{at}med.uvm.edu

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.

  • autoimmune diseases
  • systemic lupus erythematosus
  • T cells
  • inflammation
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

View Full Text

Statistics from Altmetric.com

Footnotes

  • 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 ralph.budd@med.uvm.edu.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.