The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis

Toxicol Sci. 2010 Apr;114(2):237-46. doi: 10.1093/toxsci/kfp274. Epub 2009 Nov 12.


Multiple sclerosis (MS) is an autoimmune disease characterized by peripheral activation of CD4(+) T cells that migrate into the central nervous system (CNS) and mount an autoimmune neuroinflammatory attack on myelin and oligodendrocytes. Secondary to these events, however equally destructive, is the generation of inflammatory-mediated reactive oxygen and nitrogen species generated by persistently activated microglia and astrocytes. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a basic leucine zipper transcription factor that regulates genetic expression of many protective antioxidant and detoxication enzymes. Here we describe the Nrf2 modulation of innate and adaptive immune responses in an acute autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE). Wild-type (WT) mice and Nrf2 knockout mice were immunized with myelin oligodendrocyte glycoprotein (MOG 35-55) and monitored daily for clinical scores of disease. Disruption of Nrf2 resulted in a more severe clinical course, a more rapid onset, and a greater percentage of mice with the disease. Furthermore, increased immune cell infiltration and glial cell activation in spine was observed. In conjunction, we observed increased inflammatory enzyme (iNOS, phox-47, gp91-phox, and phox-67), cytokine (IFN-gamma, IL1-b, TNF-alpha, and IL-12), and chemokine (BLC and MIG) gene expression levels in the Nrf2-deficient mice compared to the WT mice, supporting the notion that Nrf2 can modulate an autoimmune neuroinflammatory response. Our results show that the absence of Nrf2 exacerbates the development of EAE and thus suggests that activation of Nrf2 may then attenuate pathogenesis of autoimmune diseases such as MS as well as other neurodegenerative diseases that present with neuroinflammation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Chimera
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Enzymes / genetics
  • Enzymes / metabolism
  • Female
  • Gene Expression
  • Glycoproteins / administration & dosage
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology*
  • Myelin-Oligodendrocyte Glycoprotein
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / immunology*
  • Oxidative Stress
  • Peptide Fragments / administration & dosage
  • Species Specificity
  • Spinal Cord / immunology
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Enzymes
  • Glycoproteins
  • Myelin-Oligodendrocyte Glycoprotein
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Peptide Fragments
  • myelin oligodendrocyte glycoprotein (35-55)