Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema

Caspar Schiffers, Lennart K. A. Lundblad, Milena Hristova, Aida Habibovic, Christopher M. Dustin, Nirav Daphtary, Minara Aliyeva, David J. Seward, Yvonne M. W. Janssen-Heininger, Emiel F. M. Wouters, Niki L. Reynaert, Albert van der Vliet*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

Aging is associated with a gradual loss of lung function due to increased cellular senescence, decreased regenerative capacity, and impaired innate host defense. One important aspect of innate airway epithelial host defense to nonmicrobial triggers is the secretion of alarmins such as IL-33 and activation of type 2 inflammation, which were previously found to depend on activation of the NADPH oxidase (NOX) homolog DUOX1, and redox-dependent signaling pathways that promote alarmin secretion. Here, we demonstrate that normal aging of C57BL/6J mice resulted in markedly decreased lung innate epithelial type 2 responses to exogenous triggers such as the airborne allergen Dermatophagoides pteronyssinus, which was associated with marked downregulation of DUOX1, as well as DUOX1-mediated redox-dependent signaling. DUOX1 deficiency was also found to accelerate age-related airspace enlargement and decline in lung function but did not consistently affect other features of lung aging such as senescence-associated inflammation. Intriguingly, observations of age-related DUOX1 downregulation and enhanced airspace enlargement due to DUOX1 deficiency in C57BL/6J mice, which lack a functional mitochondrial nicotinamide nucleotide transhydrogenase (NNT), were much less dramatic in C57BL/6NJ mice with normal NNT function, although the latter mice also displayed impaired innate epithelial injury responses with advancing age. Overall, our findings indicate a marked aging-dependent decline in (DUOX1-dependent) innate airway injury responses to external nonmicrobial triggers, but the impact of aging on DUOX1 downregulation and its significance for age-related senile emphysema development was variable between different C57BL6 substrains, possibly related to metabolic alterations due to differences in NNT function.

Original languageEnglish
Pages (from-to)L144-L158
Number of pages15
JournalAmerican Journal of Physiology-Lung Cellular and Molecular Physiology
Volume321
Issue number1
DOIs
Publication statusPublished - Jul 2021

Keywords

  • allergen
  • epithelium
  • NADPH oxidase
  • NNT
  • type 2 cytokines
  • EPITHELIAL-CELL MIGRATION
  • NADPH OXIDASES
  • LIFE-SPAN
  • PROMOTER HYPERMETHYLATION
  • OXIDATIVE STRESS
  • IL-33 PROMOTES
  • NOX ENZYMES
  • LUNG HEALTH
  • MITOCHONDRIAL
  • EXPRESSION

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