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

Area of Science:

• Immunology
• Metabolic pathways
• Cellular respiration

Background:

• Chronic obstructive pulmonary disease (COPD) involves persistent airway inflammation and macrophage dysfunction.
• The role of macrophage bioenergetics in COPD pathogenesis and impaired antioxidant responses requires further elucidation.

Purpose of the Study:

• To investigate intrinsic metabolic defects in COPD alveolar macrophages (AMs) and monocyte-derived macrophages (MDMs).
• To determine if metabolic dysfunction drives macrophage dysfunction and redox imbalance in COPD.

Main Methods:

• Functional, metabolic, and transcriptional profiling of AMs and MDMs from COPD and healthy donors.
• Analysis of energy reserves, ATP production via glycolysis and mitochondrial respiration.
• Assessment of redox balance and expression of malic enzyme 1 (ME1) and NRF2.

Main Results:

• COPD macrophages exhibit depleted energy reserves and over-reliance on glycolysis, leading to reduced energy status.
• Impaired oxidative metabolism and redox balance were observed, linked to defective ME1 expression.
• Selective NRF2 activation improved energetic status, redox balance, and macrophage function by resetting the transcriptome.

Conclusions:

• COPD is characterized by a loss of metabolic plasticity, resulting in macrophage exhaustion and reduced redox capacity.
• Activation of the NRF2 pathway can rescue these metabolic defects in COPD macrophages.
• Targeting NRF2 may represent a promising therapeutic strategy for managing COPD-related airway inflammation.