Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Geriatrics and Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Am J Respir Cell Mol Biol. 2021 Jan;64(1):115-125. doi: 10.1165/rcmb.2020-0360OC.
Augmented glycolysis due to metabolic reprogramming in lung myofibroblasts is critical to their profibrotic phenotype. The primary glycolysis byproduct, lactate, is also secreted into the extracellular milieu, together with which myofibroblasts and macrophages form a spatially restricted site usually described as fibrotic niche. Therefore, we hypothesized that myofibroblast glycolysis might have a non-cell autonomous effect through lactate regulating the pathogenic phenotype of alveolar macrophages. Here, we demonstrated that there was a markedly increased lactate in the conditioned media of TGF-β1 (transforming growth factor-β1)-induced lung myofibroblasts and in the BAL fluids (BALFs) from mice with TGF-β1- or bleomycin-induced lung fibrosis. Importantly, the media and BALFs promoted profibrotic mediator expression in macrophages. Mechanistically, lactate induced histone lactylation in the promoters of the profibrotic genes in macrophages, consistent with the upregulation of this epigenetic modification in these cells in the fibrotic lungs. The lactate inductions of the histone lactylation and profibrotic gene expression were mediated by p300, as evidenced by their diminished concentrations in p300-knockdown macrophages. Collectively, our study establishes that in addition to protein, lipid, and nucleic acid molecules, a metabolite can also mediate intercellular regulations in the setting of lung fibrosis. Our findings shed new light on the mechanism underlying the key contribution of myofibroblast glycolysis to the pathogenesis of lung fibrosis.
由于肺肌成纤维细胞的代谢重编程，糖酵解增强对于其成纤维表型至关重要。主要的糖酵解副产物乳酸也被分泌到细胞外环境中，与肌成纤维细胞和巨噬细胞一起形成一个通常被描述为纤维化龛的空间受限部位。因此，我们假设肌成纤维细胞的糖酵解可能通过乳酸调节肺泡巨噬细胞的致病表型产生非细胞自主效应。在这里，我们证明转化生长因子-β1（TGF-β1）诱导的肺肌成纤维细胞的条件培养基和 TGF-β1 或博来霉素诱导的肺纤维化小鼠的 BAL 液（BALF）中存在明显增加的乳酸。重要的是，培养基和 BALF 促进了巨噬细胞中促纤维化介质的表达。从机制上讲，乳酸诱导巨噬细胞中成纤维基因启动子中的组蛋白乳酰化，这与这些细胞在纤维化肺中的这种表观遗传修饰的上调一致。组蛋白乳酰化和促纤维化基因表达的乳酸诱导是由 p300 介导的，这一点可以从 p300 敲低的巨噬细胞中 p300 浓度降低得到证明。总之，我们的研究表明，除了蛋白质、脂质和核酸分子外，代谢物也可以在肺纤维化的情况下介导细胞间调节。我们的发现为肌成纤维细胞糖酵解对肺纤维化发病机制的关键贡献提供了新的机制。
