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

Abstract

Inflammation and oxidative stress are well established in systemic lupus erythematosus (SLE) and are critical to the pathogenesis of autoimmune diseases. The transcription factor NF-E2 related factor 2 (Nrf2) is a central regulator of cellular anti-oxidative responses, inflammation, and restoration of redox balance. Accumulating reports support an emerging role for the regulation of Nrf2 in SLE. These include findings on the development of lupus-like autoimmune nephritis and altered immune cell populations in mice lacking Nrf2, as well as decreased Nrf2 abundance in the dendritic cells of patients with SLE. Nrf2-inducing agents have been shown to alleviate oxidative and inflammatory stress and reduce tissue injury in SLE mouse models. Since Nrf2 expression can be increased in activated T cells, the precise role of Nrf2 activation in different immune cell types and their function remains to be defined. However, targeting Nrf2 for the treatment of diseases associated with oxidative stress and inflammation, such as SLE, is promising. As investigation of Nrf2-inducing agents in clinical trials grows, defining the signaling and molecular mechanisms of action and downstream effects in response to different Nrf2-inducing agents in specific cells, tissues, and diseases, will be critical for effective clinical use.

Association of serum Nrf2 protein levels with disease activity and renal impairment in lupus nephritis

“…Therefore, targeting Nrf2 for LN may be an effective therapeutic option. In preclinical studies, Nrf2 activators such as sulforaphane, dimethyl fumarate, and bardoxolone methyl attenuated inflammation and oxidative stress in lupus mice, as well as it reduced proteinuria and protected renal function ( 4 ). Fumarate can treat discoid lupus erythematosus ( 4 ).…”

“…Excessive production of reactive oxygen species (ROS) in patients with SLE in response to noxious stimuli may affect the antioxidant capacity of the body ( 2 , 3 ). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of oxidative stress and inflammation ( 4 ); a growing number of reports in the literature support a role of Nrf2 in LN. Nrf2 is involved in anti-apoptotic, anti-inflammatory, antioxidant, epithelial-mesenchymal transition (EMT) ( 5 ), and mesenchymal fibrosis processes, all of which play important roles in the progression of LN ( 4 , 6 ).…”

“…Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central regulator of oxidative stress and inflammation ( 4 ); a growing number of reports in the literature support a role of Nrf2 in LN. Nrf2 is involved in anti-apoptotic, anti-inflammatory, antioxidant, epithelial-mesenchymal transition (EMT) ( 5 ), and mesenchymal fibrosis processes, all of which play important roles in the progression of LN ( 4 , 6 ). Nrf2-mediated oxidative stress pathways are shared among LN, diabetic nephropathy, IgA nephropathy, and other disorders, indicating that targeting Nrf2 expression may be critical to successful LN therapy ( 7 ).…”

“…Studies on Nrf2 and Nrf2 inducers in LN have focused on animal models in which the Nrf2 pathway is down-regulated in renal cells. Furthermore, Nrf2 inducers have been shown to have anti-inflammatory, antioxidant, and protective effects against renal injury in LN mice ( 4 ). Currently, clinical studies on Nrf2 have focused on advanced kidney disease, with reports indicating that Nrf2 expression correlated with the degree of renal failure and comorbidities ( 8 , 9 ) and Nrf2 expression varied among different types of immune cells and tissues ( 4 ).…”

“…Furthermore, Nrf2 inducers have been shown to have anti-inflammatory, antioxidant, and protective effects against renal injury in LN mice ( 4 ). Currently, clinical studies on Nrf2 have focused on advanced kidney disease, with reports indicating that Nrf2 expression correlated with the degree of renal failure and comorbidities ( 8 , 9 ) and Nrf2 expression varied among different types of immune cells and tissues ( 4 ). Meanwhile, regarding clinical trials, it was noted that the Nrf2 activator bardoxolone methyl did not reduce the risk of death due to ESRD in patients with type 2 diabetes and stage 4 chronic kidney disease.…”