1 Department of Respiratory Medicine, and.
2 TB Immunology Research Group, School of Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland; and.
Am J Respir Cell Mol Biol. 2018 Nov;59(5):572-579. doi: 10.1165/rcmb.2018-0162OC.
Smoking is a major risk factor driving the tuberculosis epidemic, and smokers' alveolar macrophages (AM) demonstrate significant immune defects after infection. Recently, macrophage glycolytic reprogramming has emerged as crucial in the early host immune response to Mycobacterium tuberculosis (Mtb) infection. In the present study, we sought to compare baseline metabolic characteristics and the glycolytic response to infection of human AM from smokers and nonsmokers. AM were obtained at bronchoscopy, and extracellular flux analyses were performed to determine baseline metabolic characteristics compared with human monocyte-derived macrophages (MDM). Metabolic characterization of AM from smokers and nonsmokers was performed similarly. After infection with Mtb, differences in glycolytic response were measured by extracellular flux analyses and gene expression analyses and correlated with production of glycolysis-driven IL-1β and prostaglandin E. Similar experiments were performed in cigarette smoke extract-treated MDM as an alternative model. At baseline, human AM from nonsmokers have a significantly lower extracellular acidification rate/oxygen consumption rate ratio than MDM (P < 0.05), but they retain substantial glycolytic reserve. Compared with nonsmokers' AM, smokers' AM demonstrate reduced metabolic activity, reduced glycolytic reserve (P = 0.051), and reduced spare respiratory capacity (P < 0.01). After infection with Mtb, smokers' AM have significantly reduced glycolytic response, as measured by extracellular flux analyses (P < 0.05) and glycolytic gene expression analyses. Cigarette smoke extract-treated MDM similarly demonstrate reduced metabolic activity and reserves, as well as impaired glycolytic response to infection. Human AM demonstrate metabolic plasticity that allows glycolytic reprogramming to occur after Mtb infection. In smokers, this metabolic reserve is significantly attenuated, with consequent impairment of the glycolytic response to infection.
吸烟是推动结核病流行的主要危险因素，吸烟者的肺泡巨噬细胞（AM）在感染后表现出明显的免疫缺陷。最近，巨噬细胞糖酵解重编程在宿主对结核分枝杆菌（Mtb）感染的早期免疫反应中显得至关重要。在本研究中，我们试图比较吸烟者和非吸烟者的 AM 的基线代谢特征和对感染的糖酵解反应。通过支气管镜获得 AM，并进行细胞外通量分析，以比较与人类单核细胞衍生的巨噬细胞（MDM）的基线代谢特征。同样对吸烟者和非吸烟者的 AM 进行代谢特征分析。通过细胞外通量分析和基因表达分析来测量感染 Mtb 后的糖酵解反应差异，并与糖酵解驱动的 IL-1β 和前列腺素 E 的产生相关联。在香烟烟雾提取物处理的 MDM 中进行了类似的实验作为替代模型。在基线时，非吸烟者的人 AM 的细胞外酸化率/耗氧量比率明显低于 MDM（P<0.05），但它们保留了大量的糖酵解储备。与非吸烟者的 AM 相比，吸烟者的 AM 表现出代谢活性降低、糖酵解储备减少（P=0.051）和备用呼吸能力降低（P<0.01）。感染 Mtb 后，吸烟者的 AM 的糖酵解反应明显降低，通过细胞外通量分析（P<0.05）和糖酵解基因表达分析进行测量。香烟烟雾提取物处理的 MDM 也表现出代谢活性和储备减少，以及感染时糖酵解反应受损。人 AM 表现出代谢可塑性，允许在 Mtb 感染后发生糖酵解重编程。在吸烟者中，这种代谢储备明显减弱，导致感染时的糖酵解反应受损。
