ABSTRACT
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease pathologically characterized by vascular necrosis with inflammation. During AAV development, activated neutrophils produce reactive oxygen species (ROS), leading to the aberrant formation of neutrophil extracellular traps (NETs) via NETosis and subsequent fibrinoid vascular necrosis. Nuclear factor-erythroid 2-related factor 2 (Nrf2) functions as an intracellular defense system to counteract oxidative stress by providing antioxidant properties. Herein, we explored the role of Nrf2 in the pathogenesis of AAV. The role and mechanism of Nrf2 in ANCA-stimulated neutrophils and subsequent endothelial injury were evaluated in vitro using Nrf2 genetic deletion and Nrf2 activator treatment. In corresponding in vivo studies, the role of Nrf2 in ANCA-transfer AAV and spontaneous AAV murine models was examined. Pharmacological activation of Nrf2 in vitro suppressed ANCA-induced NET formation via the inhibition of ROS. In contrast, NET formation was enhanced in Nrf2-deficient neutrophils. Furthermore, Nrf2 activation protected endothelial cells from ANC-induced NETs-mediated injury. In vivo, Nrf2 activation ameliorated glomerulonephritis in two AAV models by upregulating antioxidants and inhibiting ROS-mediated NETs. Furthermore, Nrf2 activation restrained the expansion of splenic immune cells, including T lymphocytes and limited the infiltration of Th17 cells into the kidney. In contrast, Nrf2 genetic deficiency exacerbated vasculitis in a spontaneous AAV model. Thus, the pathophysiological process in AAV may be downregulated by Nrf2 activation, potentially leading to a new therapeutic strategy by regulating NETosis.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Disease Models, Animal , Extracellular Traps , Mice, Knockout , NF-E2-Related Factor 2 , Neutrophils , Peroxidase , Reactive Oxygen Species , Animals , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Extracellular Traps/immunology , Extracellular Traps/metabolism , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics , Neutrophils/immunology , Neutrophils/metabolism , Reactive Oxygen Species/metabolism , Peroxidase/metabolism , Peroxidase/genetics , Mice , Humans , Oxidative Stress/immunology , Mice, Inbred C57BL , Endothelial Cells/immunology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Glomerulonephritis/immunology , Glomerulonephritis/pathology , Glomerulonephritis/genetics , Glomerulonephritis/metabolism , Glomerulonephritis/etiology , Antibodies, Antineutrophil Cytoplasmic/immunology , Male , Kidney/pathology , Kidney/immunology , Signal Transduction/immunologyABSTRACT
OBJECTIVES: The objective of this study was to investigate the influence of treatment with cholinesterase inhibitors (ChEIs) and calcineurin inhibitors (CNIs) on the occurrence of cramps in myasthenia gravis (MG) patients. METHODS: The frequency and duration of cramp and serum electrolytes were evaluated in 81 patients with MG. The patients were classified using Myasthenia Gravis Foundation of America postintervention status scores based on the treatment and the responsiveness to the treatment. Quantitative MG score, MG activities of daily living score, MG composite score, or MG quality of life 15 score was used to assess the health-related quality of life (QOL). RESULTS: Muscle cramps developed in 44 (54.3%) of 81 MG patients. The scores of MG activities of daily living, MG composite, or MG-QOL 15-item questionnaire in patients with cramp were significantly higher than those in patients without cramps (P = 0.002, P = 0.01, or P = 0.0022, respectively). The serum magnesium concentrations were lower in patients treated with CNI (n = 16) than in those not treated with CNI (n = 65) (P = 0.002). The probability of cramps was significantly higher in patients treated with ChEIs (≥180 mg/d) in addition to CNI than in patients who were treated with a low dose of ChEIs (≤60 mg/d) without concomitant CNI treatment (P = 0.017). CONCLUSIONS: Our data suggested that treatment with a high dose of ChEI and CNI accelerated the probability of cramps and reduced the QOL in MG patients.
