Association of Nrf2 with airway pathogenesis: lessons learned from genetic mouse models

Abstract

Nrf2 is a key transcription factor for antioxidant response element (ARE)-bearing genes involved in diverse host defense functions including redox balance, cell cycle, immunity, mitochondrial biogenesis, energy metabolism, and carcinogenesis. Nrf2 in the airways is particularly essential as the respiratory system continuously interfaces with environmental stress. Since Nrf2 was determined to be a susceptibility gene for a model of acute lung injury, its protective capacity in the airways has been demonstrated in experimental models of human disorders using Nrf2 mutant mice which were susceptible to supplemental respiratory therapy (e.g., hyperoxia, mechanical ventilation), cigarette smoke, allergens, virus, environmental pollutants, and fibrotic agents compared to wild-type littermates. Recent studies also determined that Nrf2 is indispensable in developmental lung injury. While association studies with genetic NRF2 polymorphisms supported a protective role for murine Nrf2 in oxidative airway diseases, somatic NRF2 mutations enhanced NRF2-ARE responses, and were favorable for lung carcinogenesis and chemoresistance. Bioinformatic tools have elucidated direct Nrf2 targets as well as Nrf2-interacting networks. Moreover, potent Nrf2-ARE agonists protected oxidant-induced lung phenotypes in model systems, suggesting a therapeutic or preventive intervention. Further investigations on Nrf2 should yield greater understanding of its contribution to normal and pathophysiological function in the airways.

Keywords: Antioxidant response element; Knockout mice; Lung; Nfe2l2; Oxidative stress.

Figure 1.. Inbred mouse strains classified by Nrf2 genetic variation.

(A) An illustration of three major haplotypes of murine Nrf2 (75.7–75.6 Mb) on chromosome 2 determined by hierarchical clustering of 173 single nucleotide polymorphism (SNP) from 72 inbred strains of mice (Cho et al. 2015a). Each row of the matrix represents a single inbred strain of mouse. The blue and orange filled boxes represent the panel of SNPs (columns) in Nrf2. where blue indicates the reference (C3H/HeJ) allele and yellow indicates the alternate allele. Orange indicates the third allele in the trimorphic SNP sites. Colors of the circles on top of the matrix indicate the SNP location in the structural regions (exon, intron, or flanking). (B) A phylogenetic tree for inbred strains of mice constructed from the Nrf2 haplotype analysis.