Nrf2 expression driven by Foxp3 specific deletion of Keap1 results in loss of immune tolerance in mice

Abstract

The transcription factor Nrf2 regulates oxidative stress responses. However, the specific function of Nrf2 in Tregs, the central regulators of immune homeostasis, is unclear. Here, we report an unexpected but important role of Nrf2 in Tregs. Nrf2 expression driven by Foxp3 specific deletion of Keap1 resulted in an autoinflammatory phenotype with enhanced effector T cell activation and immune cell infiltrates in the lung. While early postnatal death of mice with Foxp3 specific deletion of Keap1 was most probably due to ectopic Foxp3cre expression and subsequent Keap1 deletion in epithelial cells, bone marrow chimeras suggest that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. Moreover, Nrf2 activation was associated with a loss of Foxp3 expression, but an enhanced glucose uptake and mTOR activity in Tregs, thus mimicking a metabolic phenotype that is associated with impaired lineage stability and cell functioning.

The role of Nrf2 in acute and chronic muscle injury

“…Interestingly, this finding is consistent with the recent study showing Nrf2 as negative regulator of T reg cells (39). Importantly, our data are in a line with work by Takemoto et al in which Nrf2 transcriptional deficiency has not exacerbated inflammation in the diaphragm of mdx mice (40), the muscle which is the most severely affected in DMD.…”

“…DMD is still incurable disease and pharmacological treatment with corticosteroids, anti-inflammatory agents, is still the gold standard of care of DMD patients (39). Despite having a beneficial effect on muscle function, these drugs cause many side effects such as delayed puberty and growth, weight gain, adrenal insufficiency, and behavioral disorders (34 and T c lymphocytes contribute to the pathogenesis of DMD (6) and their functions may be regulated by Nrf2 (38), their quantity was changed neither by dystrophin nor Nrf2 deficiency.…”

Chronic arsenic exposure induces the time-dependent modulation of inflammation and immunosuppression in spleen

“…The continuous activation of MAPK in our study was beneficial to induce the formation of various immune inflammatory factors. In addition to the classic antioxidant effect of the nrf2 signaling pathway, the specific deletion of Foxp3 in Nrf2 activated mice caused the loss of immune tolerance in mice, suggesting that nrf2 signaling is involved in the regulation of immune homeostasis [ 46 ]. Nrf2 deficiency has been shown to trigger an autoimmune inflammatory response in multiple organs [ 47 , 48 ].…”

Oxidative Stress in SLE T Cells, Is NRF2 Really the Target to Treat?

“…This suggests NRF2 activation in multiple cell lineages appears to be required for sufficient anti-inflammatory effects. Our group even observed a pro-inflammatory effect of NRF2 when we specifically deleted NRF2 in T regs (26). This raises the question if it is beneficial to use NRF2 activation in SLE as a therapeutic intervention.…”

“…These proteins include enzymes mediating glutathione (GSH) synthesis, the thioredoxin enzyme system and detoxifying enzymes such as heme oxygenases, or NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition to induction of antioxidant genes, NRF2 also modulates immune responses by regulating transcription of several others including anti-inflammatory and metabolic genes in immune cells (23)(24)(25)(26). So, being a critical regulator of cellular oxidative stress responses and inflammatory reactions, it is not surprising that NRF2 is indispensable to prevent cellular damage and subsequent inflammation.…”