Altered redox regulation by Nrf2-Keap1 system in dendritic cells of systemic lupus erythematosus patients

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with inflammation and multiple organ involvement. Individually, dendritic cells (DCs) and oxidative stress have been well discussed for their critical involvement in the pathogenesis of disease but the precise impact of oxidative stress on DCs in relation to SLE disease activity is yet to be scrutinized. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is the cellular mechanism to combat increased reactive oxygen species (ROS). The current study was framed in order to understand redox regulation in DCs along with an argument in context to disease activity. Here, 23 SLE patients along with 10 healthy controls were enrolled and disease activity was calculated as the recent change in SLEDAI score. We found the percentage of circulating plasmacytoid DCs (pDCs) was increased with an increase in disease activity. Altered DCs functionality along with disease activity was further supported with the differential concentration of Type I IFNs. The disease activity was positively associated with increased levels of ROS. A relevant reason for increased ROS was further explained with the decreased levels of transcription factor Nrf2. Hence, the present study suggests that SLE specific DCs displayed elevation in ROS and this outcome might be due to impaired free radical clearance by Nrf2. Correlation studies further established an association of disease activity with increased ROS, Type I IFNs levels and decreased activity of oxidative stress regulating enzymes.

Insufficient Iron Improves Pristane-Induced Lupus by Promoting Treg Cell Expansion

“…Reducing intracellular ROS accumulation inhibits oxidative damage and the expression of apoptosis-related proteins P53 and Bax in splenic lymphocytes (37). Furthermore, ROS production of PBMCs is highly increased in SLE patients compared with healthy controls (38)(39)(40). ROS interferes with mTOR signaling to promote T cell overactivation in lupus, suggesting that ROS plays a pathogenic role in SLE development (41,42).…”

The Potential of Nrf2 Activation as a Therapeutic Target in Systemic Lupus Erythematosus

“…Plasmacytoid dendritic cells (pDCs) isolated from SLE patients with high disease activity were found to have elevated intracellular ROS compared to cells in SLE patients in remission [74]. Furthermore, Nrf2 and Keap1 levels decreased in pDCs from patients with active SLE compared to healthy controls, suggesting that regulation of oxidative stress via the Keap1/Nrf2 pathway was impaired in pDCs in these patients [74], which may contribute to the pathogenic role of pDCs in SLE.…”

“…Multiple studies have shown increased levels of oxidative stress in the blood, tissues, and immune cells of SLE patients [16,[73][74][75]. Furthermore, levels of oxidative stress correlate with disease activity.…”

Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat?

“…It is therefore not clear, how this study can be transferred to the human SLE disease. With that regard, Gautam et al found elevated ROS in SLE specific DCs, which might be due reduced clearance of ROS related to impaired levels of NRF2 (6). In addition, the association of the NRF2 -653G/A polymorphism with lupus nephritis in pediatric-onset SLE has been described (38).…”

“…Nevertheless, there is mounting evidence for a defective redox clearance in SLE. Patients with highly active disease show impaired activity of oxidative stress regulating enzymes, such as superoxide dismutase (SOD) and gluthathione peroxidase (GPX) in serum and saliva while PBMCs of active SLE patients reveal higher intracellular ROS than those of healthy controls (6)(7)(8)(9). Increased oxygen intermediates have also been identified in macrophages of lupus mice (10).…”