Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice

Takuma Suzuki, Shohei Murakami, Shyam S. Biswal, Shimon Sakaguchi, Hideo Harigae, Masayuki Yamamoto, Hozumi Motohashi

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

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 Tregindependent 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.

Original languageEnglish
Article numbere00063-17
JournalMolecular and cellular biology
Volume37
Issue number15
DOIs
Publication statusPublished - 2017 Aug 1

Keywords

  • Autoimmune diseases
  • Autoimmunity
  • Inflammation
  • KEAP1
  • NRF2
  • Scurfy mice
  • Scurfy mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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