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Adenine Nucleotide translocase 1 (ANT1) Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD

ABSTRACT: Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) has elevated ANT1 compared to normal control subjects. Ant1-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. Ant1-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional Ant1 knockout in Cx3cr1-positive monocytes and adoptive transfer of Ant1-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD

ORGANISM(S): Mus musculus

PROVIDER: GSE287944 | GEO | 2025/03/31

REPOSITORIES: GEO

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Project description:COPD is a common and disabling lung disease for which very few therapeutic options are currently available. We reasoned that global gene expression profiling of COPD lungs could reveal previously unidentified disease pathways for potential therapeutic interventions. Forty-eight human lung samples were obtained from lungs or lobes resected for small peripheral lung lesions (5 non-smokers, 21 GOLD 0, 9 GOLD 1, 10 GOLD 2 and 3 GOLD 3 patients). mRNA from the specimens was profiled using Agilent’s Functional ID v2.0 array which contains 23,720 sequences. Quantitative morphometric analysis of the specimens revealed that the samples contained a variable proportion of airways, blood vessels and parenchyma. Incorporating these data into a model relating gene expression to % predicted forced expiratory flow between 25 and 75% of forced expiratory volume (FEF 25-75 % P) revealed a signature gene set of 203 transcripts. Genes involved in extracellular matrix synthesis/degradation, oxidative stress and cell proliferation were among the up-regulated genes whereas genes which participate in nicotine metabolism, elastic fiber homeostasis and anti-inflammatory response were down-regulated. Immunohistochemistry confirmed expression of urokinase (PLAU), urokinanse receptor (PLAUR) and thrombospondin (THBS1) by alveolar macrophages and small airway epithelial cells. Genes in this pathway have been shown to be involved in transforming growth factor beta-1 (TGF?1) and matrix metalloproteinase (MMP) activation and are subject to inhibition by serpin E2. Interestingly, both TGF?1 and serpin E2 have been identified as candidate genes in COPD genetic linkage and association studies. The results thus provide a possible link between these two powerful approaches to identify potential therapeutic targets. (255 words) Forty-eight human lung samples were obtained from lungs or lobes resected for small peripheral lung lesions (5 non-smokers, 21 GOLD 0, 9 GOLD 1, 10 GOLD 2 and 3 GOLD 3 patients). mRNA from the specimens was profiled using Agilent’s Functional ID v2.0 array which contains 23,720 sequences. Quantitative morphometric analysis of the specimens revealed that the samples contained a variable proportion of airways, blood vessels and parenchyma. Incorporating these data into a model relating gene expression to % predicted forced expiratory flow between 25 and 75% of forced expiratory volume (FEF 25-75 % P) revealed a signature gene set of 203 transcripts.

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Adenine Nucleotide translocase 1 (ANT1) Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD

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