Oxidative Stress Promotes Instability of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Abstract

We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-γ, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-γ, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.

Measurement of superoxide dismutase: Clinical usefulness for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

“…Studies have shown that SOD can not only remove free radicals but also regulate immune cell function, inhibit in ammatory mediators, and regulate cell signaling [10,30]. A signi cant decrease in SOD level indicates a serious oxidative stress imbalance within the body.…”

The Influence of Antioxidants on Oxidative Stress-Induced Vascular Aging in Obesity

“…Resveratrol plays a role in reducing H 2 O 2 production [ 69 ]. In people with obesity, decreasing the level of regulatory T cells caused by consuming high-fat foods can lead to an increase in the level of oxidative stress [ 70 ]. Resveratrol has been shown to play an important role in improving T-Regs function and preventing suppression of T-Regs production [ 71 ].…”

Sirtuin family in autoimmune diseases

“…Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease involving hyperactivated neutrophils, inflammatory factors, and ROS. Shimojima et al investigated the role of Tregs in AAV and showed that SIRT1 levels, to some extent, negatively regulated the AMPK pathway through the mTOR, maintaining the stability of Tregs in AAV (144). Additionally, oxidative stress had been observed to be involved in giant cell arteritis, which was mainly maintained by the enhanced ROS production by immature neutrophils.…”