T1 Defective metabolism drives macrophage dysfunction in COPD

COPD is set to become the third leading cause of death globally by 2023. To date, we have no significant disease modifying therapies. COPD patients experience chronic inflammation and defective innate immunity, largely driven by macrophage dysfunction. In established disease, COPD macrophages have impaired phagocytosis of bacteria and apoptotic cells (efferocytosis). There is evidence of altered antioxidant responses, namely via reduced expression of the transcription factor Nrf2. Through the study of airway (AM) and peripheral monocyte-derived (MDM) macrophages recruited from patients with mild moderate and severe COPD, we questioned whether disordered metabolic processes underlie the defect in macrophage function and how this may relate to impaired antioxidant responses. We demonstrated that both AM and MDM from COPD patients have impaired bacterial phagocytosis and efferocytosis compared to Healthy Donors. Metabolic profiling, using Seahorse technology, confirmed that COPD AM and MDM have exhausted energy reserves in glycolysis and oxidative phosphorylation. Moreover, Seahorse and LC-MS (liquid chromatography mass spectrometry) revealed a persistent over reliance on glycolysis in COPD. Crucially, this apparent defect in oxidative metabolism depleted energy status and may be due to the impaired redox balance we observed in COPD. We have previously established that COPD AM display a defective transcriptional response to infection with Streptococcus pneumoniae, with failure to mount an adequate anti-oxidant response. Thus, we employed highly specific Nrf2 agonists to activate the anti-oxidant-pathway in COPD AM. This induced a reset of the COPD AM transcriptome to more closely resemble Healthy AM. Furthermore, Nrf2 activation increased TCA cycle intermediaries, improved energy status, restored redox balance and most importantly partially restored bacterial phagocytosis and efferocytosis in COPD macrophages. We have determined that both AM and MDM from COPD patients display altered bio-energetics, with metabolic exhaustion and a refractory metabolic profile. We suggest this is driving the macrophage dysfunction observed in COPD. Selective activation of the Nrf2 pathway, improves metabolism and rescues function in COPD macrophages. This highlights both the therapeutic potential for metabolic reprogramming in COPD and the role of Nrf2 activation in modulating disease behaviour in COPD macrophages.