The pathogenesis of systemic lupus erythematosus - From the viewpoint of oxidative stress and mitochondrial dysfunction

Lee, Hui-Ting; Wu, Tsai-Hung; Lin, Cheng‐Chieh; Lee, Chyou-Shen; Wei, Yau‐Huei; Tsai, Chang-Youh; Chang, Deh‐Ming

doi:10.1016/j.mito.2016.05.007

Cited by 57 publications

(44 citation statements)

References 76 publications

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“…A key role of mitochondrial dysfunction in the pathogenesis of lupus and other autoimmune diseases has been suggested (2,(21)(22)(23)(24). The results of the present study further support the notion that the use of compounds that modulate mitochondrial function and also act as antioxidants may attenuate lupusassociated organ damage and immune dysregulation associated with this disease.…”

Section: Discussionsupporting

confidence: 87%

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Blanco

Pedersen

Wang

et al. 2020

Arthritis & Rheumatology

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Objective A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models. Methods Idebenone was administered orally to MRL/lpr mice at 2 different doses (1 gm/kg or 1.5 gm/kg idebenone‐containing diet) for 8 weeks. At peak disease activity, clinical, immunologic, and metabolic parameters were analyzed and compared to those in untreated mice (n = 10 per treatment group). Results were confirmed in the lupus‐prone NZM2328 mouse model. Results In MRL/lpr mice, idebenone‐treated mice showed a significant reduction in mortality incidence (P < 0.01 versus untreated mice), and the treatment attenuated several disease features, including glomerular inflammation and fibrosis (each P < 0.05 versus untreated mice), and improved renal function in association with decreased renal expression of interleukin‐17A (IL‐17A) and mature IL‐18. Levels of splenic proinflammatory cytokines and inflammasome‐related genes were significantly decreased (at least P < 0.05 and some with higher significance) in mice treated with idebenone, while no obvious drug toxicity was observed. Idebenone inhibited neutrophil extracellular trap formation in neutrophils from lupus‐prone mice (P < 0.05) and human patients with SLE. Idebenone also improved mitochondrial metabolism (30% increase in basal respiration and ATP production), reduced the extent of heart lipid peroxidation (by one‐half that of untreated mice), and significantly improved endothelium‐dependent vasorelaxation (P < 0.001). NZM2328 mice exposed to idebenone also displayed improvements in renal and systemic inflammation, reducing the kidney pathology score (P < 0.05), IgG/C3 deposition (P < 0.05), and the gene expression of interferon, proinflammatory, and inflammasome‐related genes (at least P < 0.05 and some with higher significance). Conclusion Idebenone ameliorates murine lupus disease activity and the severity of organ damage, supporting the hypothesis that agents that modulate mitochondrial biologic processes may have a therapeutic role in human SLE.

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Section: Discussionsupporting

confidence: 87%

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Blanco

Pedersen

Wang

et al. 2020

Arthritis & Rheumatology

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“…In patients with SLE, ROS that are primarily derived from the mitochondria of lymphocytes, vascular endothelial cells, and erythrocytes have been involved in the apoptosis of T cell and the pathogenesis of SLE [29,[34][35][36]. Similarly, the rate of eryptosis was positively correlated with the ROS abundance as shown in this study.…”

Section: Discussionsupporting

confidence: 74%

Eryptosis as an Underlying Mechanism in Systemic Lupus Erythematosus-Related Anemia

Jiang

Bian²,

Ma³

et al. 2016

Cell Physiol Biochem

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Background: The progression of systemic lupus erythematosus (SLE) leads to anemia in patients, adversely affecting prognosis. The diverse causes of anemia may include excessive eryptosis or premature suicidal erythrocyte death characterized by cell shrinkage and phosphatidylserine (PS) exposure on the cell surface. The present study explored if SLE enhances eryptosis and the underlying mechanisms. Materials and Methods: Eryptosis was assessed using flow cytometry in healthy volunteers (n = 20) and anemic patients hospitalized for SLE (n = 22), for parameters including PS exposure, cell volume, cytosolic calcium ion (Ca²⁺) levels and reactive oxygen species (ROS) and ceramide abundance. These indicators were measured in erythrocytes of experimental subjects and erythrocytes treated with plasma from healthy volunteers or SLE patients. Results: The hemoglobin and hematocrit levels were significantly lower in anemic SLE patients than in healthy volunteers (***p<0.001, p<0.001, respectively). The percentage of PS-exposing erythrocytes was significantly higher in SLE patients than in healthy volunteers (p<0.001), accompanied by an increase in cytosolic Ca²⁺ levels, oxidative stress. The measurements of PS and Ca²⁺ levels were significantly higher in the erythrocytes of healthy volunteers following incubation in plasma of SLE patients than in plasma of healthy volunteers for 24h (***p<0.001, *p<0.05 respectively). Conclusion: Eryptosis is enhanced in SLE and may contribute to anemia. The probable underlying mechanisms may be an excessive formation of ROS in erythrocytes. Also, some plasma components may trigger eryptosis by increasing the cytosolic Ca²⁺ concentration.

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“…Due to excessive ROS, damaged melanocytes may go through apoptosis, and proteins altered by oxidative stress can act as autoantigens; these released autoantigens can then induce autoimmune responses in vitiligo patients . The role of oxidative stress in the disease process has been reported in rheumatic disorders: excessive oxidative stress can initiate and/or promote the autoimmune response found in rheumatic disorders . Vitiligo patients, being genetically susceptible to abnormal ROS generation and having an inadequate antioxidant defense, may be predisposed to rheumatic disorders initiated or promoted by oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Increased risk of comorbid rheumatic disorders in vitiligo patients: A nationwide population‐based study

Choi

Eun

Choi

et al. 2017

The Journal of Dermatology

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Vitiligo is a common acquired depigmentation disorder. Previous studies have shown that vitiligo is associated with a variety of autoimmune disorders. However, a large-scale epidemiological study focused on comorbid rheumatic disorders has not been undertaken. To clarify the associations between vitiligo and various rheumatic disorders, we performed a cross-sectional study using data from the Korean National Health Insurance claims database. Between 2009 and 2013, totals of 86 210 patients with vitiligo and 172 420 age- and sex-matched controls without vitiligo were enrolled in this study. Vitiligo patients were found to be at increased risk of systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome and rheumatoid arthritis, but no significant association was found between vitiligo and dermatomyositis/polymyositis, Behçet's disease or ankylosing spondylitis. Subgroup analysis showed an increased risk of dermatomyositis/polymyositis in male and ankylosing spondylitis in female vitiligo patients. The risks of dermatomyositis/polymyositis or ankylosing spondylitis were higher in young vitiligo patients. Our study confirms a significant association between vitiligo and rheumatic disorders. Differences in comorbid rheumatic disorders by age group and sex suggest the need for patient-specific approaches. Careful consideration of rheumatic disorders is required for the proper management of comorbidities in vitiligo patients.

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The pathogenesis of systemic lupus erythematosus - From the viewpoint of oxidative stress and mitochondrial dysfunction

Cited by 57 publications

References 76 publications

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone

Eryptosis as an Underlying Mechanism in Systemic Lupus Erythematosus-Related Anemia

Increased risk of comorbid rheumatic disorders in vitiligo patients: A nationwide population‐based study

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