Alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease

Background: Metabolic plasticity involving shifts between mitochondrial respiration and glycolysis is emerging as a crucial component of efficient innate immune cell responses. Alveolar macrophages (AMs), the most abundant antigen-presenting cells in the lung, are dramatically increased in the lungs of patients with chronic obstructive pulmonary disease (COPD). However, COPD AMs exhibit dysfunctional responses to infection with lower phagocytic ability and impairment of mitochondrial reactive oxygen species (ROS) generation. Little is known about the mitochondrial function or respiration of these cells and whether alterations in their mitochondrial or glycolytic activities may contribute to the pathogenesis of COPD. In this study, utilizing AMs isolated from the bronchoalveolar lavage fluid (BALF) of subjects with COPD, smokers and healthy non-smoker controls, we demonstrate that BAL macrophages from individuals with COPD have altered expression of mitochondrial-related genes from MitoCarta 2.0 and severely blunted maximal respiration, spare respiratory capacities and compensatory glycolytic rates when compared to smokers and healthy controls. We demonstrate for the first time that such impaired immunometabolic activities associate with the degree of lung function impairment, as defined by %FEV1 in these patients. Comparison of gene expression in alveolar macrophages of normal non-smokers and normal smokers and smokers with COPD The Mito Carta 2.0 website can be found at https://www.broadinstitute.org/scientific-community/science/programs/metabolic-disease-program/publications/mitocarta/mitocarta-in-0/