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Role of NRF2 in immune modulator expression in developing lung.

Authors :
Mishra R
Nawas AF
Mendelson CR
Source :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Aug; Vol. 35 (8), pp. e21758.
Publication Year :
2021

Abstract

After birth, the alveolar epithelium is exposed to environmental pathogens and high O <subscript>2</subscript> tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPβ and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPβ, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.<br /> (© 2021 Federation of American Societies for Experimental Biology.)

Details

Language :
English
ISSN :
1530-6860
Volume :
35
Issue :
8
Database :
MEDLINE
Journal :
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Publication Type :
Academic Journal
Accession number :
34245611
Full Text :
https://doi.org/10.1096/fj.202100129RR