The role of macrophage-fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis
The role of macrophage-fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis
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DOI：
10.1038/s41374-021-00701-7
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发表时间：
2021-11-13
影响因子：
5
通讯作者：
Xing, Shunpeng
中科院分区：
文献类型：
--
作者：
Xu, Qiaoyi;Mei, Shuya;Xing, Shunpeng
本研究表明，脂多糖可促进肺巨噬细胞中JNK信号通路的激活以及内源性肿瘤坏死因子-α（TNF-α）的分泌，进而通过激活6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3（PFKFB3），推动肺成纤维细胞的有氧糖酵解并促进乳酸生成。这些研究结果提示，肺巨噬细胞与成纤维细胞之间的炎症 - 代谢相互作用，可能在脂多糖诱导的肺纤维化过程中发挥关键作用。
近期有证据表明，脂多糖（LPS）诱导的肺成纤维细胞有氧糖酵解与脓毒症肺纤维化的发病机制密切相关。然而，其潜在机制仍不明确。在本研究中，我们证实脂多糖可促进肺巨噬细胞中c-Jun氨基末端激酶（JNK）信号通路的激活以及内源性肿瘤坏死因子-α（TNF-α）的分泌。这反过来又可通过激活PFKFB3，显著促进肺成纤维细胞的有氧糖酵解并增加乳酸生成。用TNF-α或内源性TNF-α（脂多糖刺激后巨噬细胞的细胞上清液）培养人肺成纤维细胞MRC-5细胞系，均可增强有氧糖酵解并增加乳酸生成。用JNK通路抑制剂处理巨噬细胞、给予TNF-α受体1（TNFR1）小干扰RNA（siRNA）、使用PFKFB3抑制剂，或用成纤维细胞特异性短发夹RNA（shRNA）沉默PFKFB3，均可阻止这些效应。此外，抑制TNF-α分泌和PFKFB3表达可在体内预防脂多糖诱导的肺纤维化。总之，本研究揭示了脂多糖诱导巨噬细胞分泌TNF-α可启动成纤维细胞的有氧糖酵解和乳酸生成，这意味着肺巨噬细胞与成纤维细胞之间的炎症 - 代谢相互作用，可能在脂多糖诱导的肺纤维化中发挥重要作用。
This study demonstrates that lipopolysaccharide promotes activation of the JNK signaling pathway and endogenous TNF-alpha secretion in pulmonary macrophages, which facilitates lung fibroblast aerobic glycolysis and lactate production through PFKFB3 activation. These findings suggests that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in lipopolysaccharide-induced pulmonary fibrosis.Recent evidence has shown that lipopolysaccharide (LPS)-induced aerobic glycolysis of lung fibroblasts is closely associated with the pathogenesis of septic pulmonary fibrosis. Nevertheless, the underlying mechanism remains poorly defined. In this study, we demonstrate that LPS promotes c-Jun N-terminal kinase (JNK) signaling pathway activation and endogenous tumor necrosis factor-alpha (TNF-alpha) secretion in pulmonary macrophages. This, in turn, could significantly promote aerobic glycolysis and increase lactate production in lung fibroblasts through 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) activation. Culturing human lung fibroblast MRC-5 cell line with TNF-alpha or endogenous TNF-alpha (cell supernatants of macrophages after LPS stimulation) both enhanced the aerobic glycolysis and increased lactate production. These effects could be prevented by treating macrophages with JNK pathway inhibitor, by administering TNF-alpha receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-alpha secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-alpha could initiate fibroblast aerobic glycolysis and lactate production, implying that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in LPS-induced pulmonary fibrosis.