Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis.
Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis.
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DOI：
10.1152/ajplung.00235.2017
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发表时间：
2017-08
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影响因子：
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通讯作者：
N. Xie;H. Cui;Jing Ge;Sami Banerjee;Sijia Guo;Shubham Dubey;E. Abraham;Rui‐Ming Liu;Gang Liu
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文献类型：
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作者：
N. Xie;H. Cui;Jing Ge;Sami Banerjee;Sijia Guo;Shubham Dubey;E. Abraham;Rui‐Ming Liu;Gang Liu
代谢重编程与巨噬细胞激活有着内在的联系。已知肺泡巨噬细胞在肺纤维化的发病机制中发挥重要作用。然而，仍然缺乏这些细胞表达谱的系统表征。此外，主要的代谢程序及其对细胞表型的调节是完全未知的。在本研究中，我们全面分析了实验性肺纤维化小鼠肺泡巨噬细胞的表达谱和主要代谢程序。我们发现，来自博莱霉素和活性 TGF-β1 诱导的纤维化小鼠肺的肺泡巨噬细胞表现出主要促纤维化的 M2 样特征，与明确定义的 M1 或任何 M2 亚型不同。更重要的是，我们发现纤维化的肺泡巨噬细胞糖酵解增强，这可能归因于多种关键糖酵解介质表达的增强。我们还发现这些细胞中脂肪酸氧化上调。然而，与典型的IL-4诱导的巨噬细胞M(IL-4)相反，纤维化肺泡巨噬细胞的促纤维化M2样特征并不依赖于脂肪酸氧化和合成或脂肪分解，而是依赖于糖酵解。此外，谷氨酰胺分解是一种与多种病理有关的关键代谢程序，对于这些巨噬细胞的促纤维化 M2 样表型来说并不是必需的。总之，我们的研究确定了来自纤维化肺的肺泡巨噬细胞的独特表达和代谢特征，并表明糖酵解抑制是治疗肺纤维化的有效抗纤维化策略。
Metabolic reprogramming has been intrinsically linked to macrophage activation. Alveolar macrophages are known to play an important role in the pathogenesis of pulmonary fibrosis. However, systematic characterization of expression profile in these cells is still lacking. Furthermore, main metabolic programs and their regulation of cellular phenotype are completely unknown. In this study, we comprehensively analyzed the expression profile and main metabolic programs in alveolar macrophages from mice with or without experimental pulmonary fibrosis. We found that alveolar macrophages from both bleomycin and active TGF-β1-induced fibrotic mouse lungs demonstrated a primarily profibrotic M2-like profile that was distinct from the well-defined M1 or any of the M2 subtypes. More importantly, we found that fibrotic lung alveolar macrophages assumed augmented glycolysis, which was likely attributed to enhanced expression of multiple key glycolytic mediators. We also found that fatty acid oxidation was upregulated in these cells. However, the profibrotic M2-like profile of fibrotic lung alveolar macrophages was not dependent on fatty acid oxidation and synthesis or lipolysis, but instead on glycolysis, in contrast to the typical IL-4-induced macrophages M(IL-4). Additionally, glutaminolysis, a key metabolic program that has been implicated in numerous pathologies, was not required for the profibrotic M2-like phenotype of these macrophages. In summary, our study identifies a unique expression and metabolic profile in alveolar macrophages from fibrotic lungs and suggests glycolytic inhibition as an effective antifibrotic strategy in treating lung fibrosis.