Transcription factor NRF2 as a key modulator of immune response

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in immune regulation by promoting antioxidant defenses, modulating inflammation, supporting immune cell function, and influencing autoimmune responses. Dysregulation of NRF2 signaling is implicated in the pathogenesis of autoimmune diseases and chronic inflammatory conditions. NRF2 activators, through their anti-inflammatory and antioxidant properties, have shown potential therapeutic benefits in preclinical and clinical studies for diseases characterized by dysregulated inflammation and oxidative stress such as multiple sclerosis (MS). MS is an autoimmune, neurodegenerative, and inflammatory disease of the central nervous system (CNS). In our model of MS, experimental autoimmune encephalomyelitis (EAE), we have investigated the role of NRF2 activators on several immune cell types important for the pathology of CNS autoimmunity. Ethyl pyruvate (EP), a redox analog of MS drug dimethyl fumarate, has been proven to have beneficial effects in EAE, by suppressing encephalitogenic T cells and macrophages and inducing tolerogenic properties in dendritic cells (DCs). In a recent study, we have shown that EP achieves its effects in DCs by increasing the expression of several NRF2 downstream genes and by decreasing the expression of NF-kB genes, suggesting that the tolerogenic effect of EP is achieved through the activation of the NRF2 signaling pathway. Another tested substance, named SB140, is a derivative of cholic bile acid. This compound was tested in immune cells implicated in the pathogenesis of EAE: microglia and encephalitogenic T cells, and it was shown to have anti-inflammatory effects. These results demonstrate that both agents have potent immunomodulatory effects and suggest that they act as NRF2 activators. Both EP and SB140 are indicated as promising therapeutics in MS, but also in other diseases mediated by inflammation and oxidative stress, and thus, their role should be further investigated.