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The role of macrophage–fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis

Abstract

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-α (TNF-α) 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-α or endogenous TNF-α (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-α receptor 1 (TNFR1) siRNA, PFKFB3 inhibitor, or by silencing PFKFB3 with fibroblasts-specific shRNA. In addition, the inhibition of TNF-α secretion and PFKFB3 expression prevented LPS-induced pulmonary fibrosis in vivo. In conclusion, this study revealed that LPS-induced macrophage secretion of TNF-α 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.

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Fig. 1: LPS induces TNF-α secretion in macrophages (RAW264.7) via JNK pathway activation.
Fig. 2: TNF-α promotes aerobic glycolysis and lactate production in lung fibroblasts.
Fig. 3: TNF-α increases PFKFB3 expression in lung fibroblasts.
Fig. 4: Inhibition of PFKFB3 precludes TNF-α-induced aerobic glycolysis and lactate production in lung fibroblasts.
Fig. 5: Inhibition of TNF-α secretion and PFKFB3 expression precludes LPS-induced pulmonary fibrosis in vivo.
Fig. 6: The diagram of macrophage-fibroblast interaction in LPS-induced pulmonary fibrosis.

Data availability

All datasets generated or analyzed during the current study are not publicly available as some of them are involved in our ongoing studies.

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Author contributions

Q.X. and S.M. performed most of the experiments and were major contributors to this manuscript. Z.H. and S.X. designed the study and provided guidance for the implementation of the study. F.N. provided assistance in writing the manuscript. J.F. and Z.Z. took charge of data analysis. J.Z. performed part of the animal experiments. X.Q. helped with the cell metabolism assay. Y.G. participated in the design of the study and provided guidance for project implementation. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, No.81970059 and 81770060) and the Natural Science Foundation of Shanghai 2020 “Science and Technology Innovation Action Plan” (20ZR1433000). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Correspondence to Zhengyu He or Shunpeng Xing.

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All animals used were approved by the Animal Care and Use Committee of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine (RJ2021-0126).

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Xu, Q., Mei, S., Nie, F. et al. The role of macrophage–fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis. Lab Invest 102, 432–439 (2022). https://doi.org/10.1038/s41374-021-00701-7

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