Activation of NRF2 Helps Lethal Autoimmune Inflammation in Scurfy Mice
The transcription factor NRF2 (nuclear factor [erythroid-derived 2]-like two ) plays critical roles in the defense mechanisms against oxidative stress and mediates anti inflammatory activities under different pathological conditions. Recent research demonstrated that the breakdown of regulatory T cells (Tregs) is linked to the initiation and development of various autoimmune disorders. To ascertain the Treg-independent effect of NRF2 stimulation on autoimmune inflammation, we analyzed scurfy (Sf) mice, which are deficient in Tregs and succumb to acute multiorgan inflammation by 4 months old. We found that systemic manipulation of NRF2 from Keap1 (Kelch-like ECH-associated protein ) knockdown ameliorated tissue inflammation and lethality from Sf mice. Activated T cells and their cytokine production were accordingly diminished by Keap1 knockdown. By comparison, NRF2 activation via mobile lineage-specific Keap1 disturbance (i.e., in T cells, myeloid cells, and dendritic cells) reached only partial or no progress from the inflammatory status of Sf mice. Our results suggest that systemic manipulation of NRF2 inhibits effector T cell actions individually of Tregs and that NRF2 stimulation in several cell lineages seems to be needed for adequate anti-inflammatory consequences. This analysis highlights the potential therapeutic program of NRF2 inducers in autoimmune disorders that are accompanied by Treg dysfunction.Details: KEAP1; NRF2; autoimmune disorders; autoimmunity; inflammation; scurfy mice; scurfy mouse.