The Role of Nrf2 in the Response to Normal Tissue Radiation Injury

Abstract

The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell’s response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2’s role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD5030. An Nrf2 deficiency drives LT-HSCs from a quiescent to a proliferative state. This results in hematopoietic exhaustion and reduced engraftment after myoablative irradiation. The question of whether induction of Nrf2 in LT-HSC enhances hematopoietic reconstitution after bone marrow transplantation is not yet resolved. Irradiation of the lung induces pulmonary pneumonitis and fibrosis. Loss of Nrf2 promotes TGF-β/Smad signaling that induces ATF3 suppression of Nrf2-mediated target gene expression. This, in turn, results in elevated reactive oxygen species (ROS) and isolevuglandin adduction of protein that impairs collagen degradation, and may contribute to radiation-induced chronic cell injury. Loss of Nrf2 impairs ΔNp63 stem/progenitor cell mobilization after irradiation, while promoting alveolar type 2 cell epithelial-mesenchymal transitions into myofibroblasts. These studies identify Nrf2 as an important factor in the radiation response of normal tissue.

Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis

“…LCE s, SPRP , KRT ) [ 15 , [23] , [24] , [25] , [26] , 28 , 30 , 31 ]. Strikingly, NRF2 activation also occurs in response to exposure to IR, consistent with the crucial involvement of free radical/ROS formation in driving the oxidative and genotoxic stress that underlies IR-mediated tissue damage [ [32] , [33] , [34] , [35] , [36] , [37] ]. Therefore, we tested the feasibility of NRF2 activation for skin radioprotection in a preclinical model, with the ultimate goal of translating said findings to benefit cancer patients receiving RT.…”

“…The concept of NRF2-directed topical radioprotection and prevention of radiation-induced dermatitis has remained largely unexplored [ 1 , [33] , [34] , [35] , [36] , [37] , [48] , [49] , [50] ]. Herein, we have elucidated the critical role that NRF2 plays in mitigating IR-induced damage and tested the efficacy of topical application of bixin to negate the effects of RT in non-tumor tissue, specifically radiation-induced dermatitis.…”

LPAR2 receptor activation attenuates radiation‐induced disruption of apical junctional complexes and mucosal barrier dysfunction in mouse colon

“…PBI‐BM5‐induced oxidative stress was associated with modulation of Nrf2 and antioxidant gene expression. NRF2 is a transcription factor critical for the expression of antioxidant genes 50,51 . Immunofluorescence imaging, immunoblot analysis, and Nrf2 mRNA measurement by RT‐qPCR indicated that PBI‐BM5 caused a significant reduction of Nrf2 expression, which was prevented by RP1 at 24 hours post‐irradiation.…”

Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications

“…They found that MyD88 was instrumental for regulating inflammatory processes that aid in recovery from radiation [ 55 , 64 ]. The activation of cGMP–AMP synthase–stimulator of interferon genes (cGAS-STING) signaling and ROS/RNS also plays an important role in lung injury mediated by non-infectious inflammatory processes [ 65 , 66 ]. The major signaling pathways involved in immunotherapy-induced RRP are shown in Fig.…”