NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease
Eilíse M. Ryan, Pranvera Sadiku, Patrícia Coelho, Emily Watts, Ailiang Zhang, Andrew J.M. Howden, Manuel A. Sánchez-García, Martin A. Bewley, Joby Cole, Brian J. McHugh, Wesley Vermaelen, Bart Ghesquière, Peter Carmeliet, Giovanny Rodriguez Blanco, Alex von Kriegsheim, Yolanda Sánchez, William L. Rumsey, James F. Callahan, George Cooper, Nick Parkinson, J. Kenneth Baillie, Doreen A. Cantrell, John McCafferty, Gourab Choudhury, Dave Singh, David H. Dockrell, Moira K. B. Whyte, Sarah R. Walmsley
Abstract
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.