NRF2 activation reprogrammes defects in oxidative metabolism to restore macrophage function in COPD

Eilise Ryan, Pranvera Sadiku, Patricia Coelho, Emily R Watts, Ailiang Zhang, Andrew J M Howden, Manuel Alejandro Sanchez Garcia, Martin A. Bewley, Joby Cole, Brian McHugh, Wesley Vermaelen, Bart Ghesquiere, Peter Carmeliet, Giovanny Rodriguez Blanco, Alexander von Kriegsheim, Yolanda Sanchez, William Rumsey, James F Callahan, George Cooper, Nicholas ParkinsonJ Kenneth Baillie, Doreen Cantrell, John McCafferty, Gourab Choudhury, David Singh, David H Dockrell, Moira K B Whyte, Sarah R Walmsley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Rationale: COPD (Chronic Obstructive Pulmonary Disease) 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 (AM) and peripheral monocyte-derived (MDM) macrophages, we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance.
Methods: AM and MDM from COPD and healthy donors underwent functional, metabolic and transcriptional profiling.
Results: We observe that AM and MDM from COPD donors display a critical depletion in glycolytic and mitochondrial respiration derived energy reserves and an over reliance 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, malic enzyme 1, a known target of the anti-oxidant transcription factor NRF2. Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance and a recovery of macrophage function.
Conclusion: 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
JournalAmerican Journal of Respiratory and Critical Care Medicine
Early online date1 Feb 2023
Publication statusE-pub ahead of print - 1 Feb 2023


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