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Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr
Karen A Fortner1, Luz P Blanco2, Iwona Buskiewicz3
1Vermont Center for Immunology and Infectious Diseases, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, USA.
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.
Insights
Targeting mitochondrial reactive oxygen species (mROS) with antioxidants like MitoQ may offer new therapeutic avenues for lupus. This approach reduced key disease markers in a mouse model, suggesting a complementary role to traditional immunosuppression.
Area of Science:
- Immunology
- Mitochondrial Biology
- Rheumatology
Background:
- Lupus is associated with mitochondrial dysfunction and increased mitochondrial reactive oxygen species (mROS) in immune cells.
- mROS contributes to cellular damage, MAVS oligomerization, type I interferon production, and neutrophil extracellular trap (NET) formation in lupus.
- NETs are implicated in lupus pathogenesis and renal damage.
Purpose of the Study:
- To investigate the therapeutic potential of targeting mROS in lupus.
- To evaluate the efficacy of a mitochondria-targeted antioxidant, MitoQ, in a lupus mouse model.
Main Methods:
- Lupus-prone MRL-lpr mice were treated with MitoQ in drinking water from weaning for 11 weeks.
- Assessed neutrophil ROS production, NET formation, MAVS oligomerization, serum IFN-I levels, autoantibody production, and renal function.
Main Results:
- MitoQ treatment significantly reduced neutrophil ROS and NET formation.
- Decreased MAVS oligomerization and serum IFN-I were observed in treated mice.
- MitoQ administration led to reduced immune complex formation in kidneys, without altering serum autoantibody levels.
Conclusions:
- Targeting mROS with antioxidants like MitoQ shows promise as a therapeutic strategy for lupus.
- This approach may complement traditional immunosuppressive therapies by mitigating key pathological processes.
- Further research into antioxidant-based therapies for lupus is warranted.
