NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease

Eilise M. Ryan, Pranvera Sadiku, Patricia Coelho, Emily R. Watts, Ailiang Zhang, Andrew J. M. Howden, Manuel A. Sanchez-Garcia, Martin Bewley, Joby Cole, Brian J. McHugh, Wesley Vermaelen, Bart Ghesquiere, Peter Carmeliet, Giovanny Rodriguez Blanco, Alex Von Kriegsheim, Yolanda Sanchez, William Rumsey, James F. Callahan, George Cooper, Nicholas ParkinsonKenneth Baillie, Doreen A. Cantrell, John McCafferty, Gourab Choudhury, Dave Singh, David H. Dockrell, Moira K. B. Whyte (Lead / Corresponding author), Sarah R. Walmsley (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
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Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance.

Methods: AMs and MDMs from donors with COPD and healthy donors underwent functional, metabolic, and transcriptional profiling.

Measurements and Main Results: We observed that AMs and MDMs from donors with COPD display a critical depletion in glycolytic- and mitochondrial respiration-derived energy reserves and an overreliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH-generating enzyme, ME1 (malic enzyme 1), a known target of the antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2). Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance, and recovery of macrophage function.

Conclusions: In COPD, an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity, which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

Original languageEnglish
Pages (from-to)998-1011
Number of pages14
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume207
Issue number8
Early online date1 Feb 2023
DOIs
Publication statusPublished - 15 Apr 2023

Keywords

  • COPD
  • macrophage
  • malic enzyme 1
  • metabolism
  • nuclear factor erythroid 2–related factor 2

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

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