Related Experiment Video
Updated: Mar 2, 2026
The bm12 Inducible Model of Systemic Lupus Erythematosus SLE in C57BL/6 Mice
Published on: November 1, 2015
Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice
Takuma Suzuki1,2, Shohei Murakami1, Shyam S Biswal3
1Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
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.
Insights
Systemic activation of nuclear factor erythroid-derived 2-like 2 (NRF2) reduces autoimmune inflammation independently of regulatory T cells (Tregs). NRF2 activation in multiple cell types is needed for significant anti-inflammatory effects.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Regulatory T cells (Tregs) dysfunction is linked to autoimmune diseases.
- Nuclear factor erythroid-derived 2-like 2 (NRF2) has antioxidant and anti-inflammatory roles.
- The Treg-independent function of NRF2 in autoimmunity requires further investigation.
Purpose of the Study:
- To investigate the Treg-independent impact of NRF2 activation on autoimmune inflammation.
- To determine the role of NRF2 in regulating T cell activity during autoimmune responses.
- To assess the therapeutic potential of NRF2 activation in autoimmune diseases.
Main Methods:
- Utilized scurfy (Sf) mice, which lack functional Tregs and develop severe multiorgan inflammation.
- Systemically activated NRF2 via Kelch-like ECH-associated protein 1 (Keap1) knockdown in Sf mice.
- Investigated cell lineage-specific NRF2 activation by disrupting Keap1 in T cells, myeloid cells, and dendritic cells.
Main Results:
- Systemic NRF2 activation significantly ameliorated tissue inflammation and reduced mortality in Sf mice.
- Keap1 knockdown led to decreased activated T cells and their cytokine production.
- Cell lineage-specific NRF2 activation provided only partial or no improvement in inflammatory status.
Conclusions:
- Systemic NRF2 activation suppresses effector T cell activity independently of Tregs.
- Nrf2 activation across multiple cell lineages is crucial for potent anti-inflammatory effects.
- NRF2 inducers may offer a therapeutic strategy for autoimmune diseases with Treg dysfunction.
