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.
Highlights
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic, epigenetic, environmental, hormonal, and immune regulatory factors [1]
Regulation of mitogen activated protein kinases (MAPKs) signaling by pharmacologic and genetic approaches alters NF-E2 related factor 2 (Nrf2) transcriptional activation [28], but substitution of specific Nrf2 residues phosphorylated by MAPKs with alanine, resulted in limited effects on Nrf2 transcriptional activation [25]. These findings suggest that phosphorylation at specific residues may not play solitary roles in Nrf2 function but rather play a part in a complex interplay of multiple signaling events Metabolites 2022, 11, x FOR PEER REaVnIEdWNrf2 modifications involved in its activation
Whether the beneficial effects of Nrf2 induction are indirectly related to the alleviation of stress or by direct transcriptional regulation in immune cells, remains to be defined
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic, epigenetic, environmental, hormonal, and immune regulatory factors [1]. Nrf is a central regulator of cytoprotection and redox homeostasis in cells This is accomplished through induction of Nrf target genes, which include enzymes involved in antioxidative responses and phase II detoxification processes. Nrf forms heterodim oefr2s3 with small Maf proteins and binds to antioxidant-response element (ARE) sites in the promoter regions of its target genes to initiate transcription. Stress simultaneproaches alters Nrf transcriptional activation [28], but substitution of specific Nrf residues phosphorylated by MAPKs with alanine, resulted in limited effects on Nrf transcriptional activation [25] These findings suggest that phosphorylation at specific residues may not play solitary roles in Nrf function but rather play a part in a complex interplay of multiple signaling events and Nrf modifications involved in its activation. Other Nrf2-induced cytoprotective mechanisms include glutathione conjugation to endogenous reactive and xenobiotic molecules by glutathione-S-transferases for detoxification [38]
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