Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

  • Suzuki T
  • Murakami S
  • Biswal S
  • et al.
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Abstract

The transcription factor NRF2 (nuclear factor [erythroid-derived 2]-like 2) plays crucial roles in the defense mechanisms against oxidative stress and mediates anti-inflammatory actions under various pathological conditions. Recent studies showed that the dysfunction of regulatory T cells (Tregs) is directly linked to the initiation and progression of various autoimmune diseases. To determine the Treg-independent impact of NRF2 activation on autoimmune inflammation, we examined scurfy (Sf) mice, which are deficient in Tregs and succumb to severe multiorgan inflammation by 4 weeks of age. We found that systemic activation of NRF2 by Keap1 (Kelch-like ECH-associated protein 1) knockdown ameliorated tissue inflammation and lethality in Sf mice. Activated T cells and their cytokine production were accordingly decreased by Keap1 knockdown. In contrast, NRF2 activation through cell lineage-specific Keap1 disruption (i.e., in T cells, myeloid cells, and dendritic cells) achieved only partial or no improvement in the inflammatory status of Sf mice. Our results indicate that systemic activation of NRF2 suppresses effector T cell activities independently of Tregs and that NRF2 activation in multiple cell lineages appears to be required for sufficient anti-inflammatory effects. This study emphasizes the possible therapeutic application of NRF2 inducers in autoimmune diseases that are accompanied by Treg dysfunction.

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Suzuki, T., Murakami, S., Biswal, S. S., Sakaguchi, S., Harigae, H., Yamamoto, M., & Motohashi, H. (2017). Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice. Molecular and Cellular Biology, 37(15). https://doi.org/10.1128/mcb.00063-17

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