Transcriptional programming of alveolar macrophages reveals major changes in lipid metabolism in COPD

Rationale: Immune cells play a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Albeit changes in distribution and cellular functions of major immune cells, such as alveolar macrophages (AMs) and neutrophils have been established, we still do not fully understand their transcriptional reprogramming and contribution to the pathophysiology of COPD. Objective: To determine changes in immune cell type distribution, transcriptional reprogramming and lipid metabolism in the bronchoalveolar lavage (BAL) of COPD patients. Methods: Multi-color flow cytometry (MCFC) was applied using most current cell-type-determining markers to BAL samples from 29 controls and 30 COPD patients at different clinical stages. Whole transcriptomes and lipidomes were analyzed in sorted CD45+Lin-HLA-DR+CD66b-Autofluoreschencehi AMs. Measurements and Main Results: Neutrophil, group 1 and group 2 innate lymphoid cell (ILC), but not AM absolute cell numbers were significantly increased in COPD patients. Focusing on AMs as the largest cell type in the alveolar space, we defined global transcriptional reprogramming and detected significant changes between controls and COPD patients in genes involved in lipid metabolism. Based on these findings, lipidomic assessment of a total of 249 lipid species in sorted AMs revealed changes of cholesteryl ester (CE), monoacylglycerols (MAG) and phosphatidylcholines (PC) in a stage-dependent manner.
Conclusion:
The combination of MCFC, transcriptomics and lipidomics demonstrated changes in cell type distribution, significant transcriptional reprogramming and disease stage-dependent changes of AM lipid metabolism as a novel hallmark of COPD.