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Histone methyltransferase SETD2 inhibits M1 macrophage polarization and glycolysis by suppressing HIF-1α in sepsis-induced acute lung injury

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Abstract

Sepsis is a severe syndrome caused by the imbalance of the host response to infection, accompanied by multiple organ damage, especially acute lung injury. SET Domain-Containing 2 (SETD2) is a methyltransferase catalyzing H3 lysine 36 trimethylation (H3K36me3) that regulates multiple biological processes. This study focused on explicating the action of SETD2 on macrophage function in sepsis and the precise mechanism involved. Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting were used to determine expression. Luciferase reporter assay and chromatin immunoprecipitation assay were conducted to detect the binding of SETD2 or H3K36me3 with the hypoxia-inducible factor 1, alpha subunit (Hif1a) gene. A sepsis-induced acute lung injury model was constructed via cecal ligation and puncture (CLP). SETD2 was decreased in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Besides, SETD2 suppressed M1 macrophage polarization and glycolysis caused by LPS. HIF-1α was enhanced in RAW 264.7 cells stimulated by LPS and inversely related to SETD2 expression. In addition, SETD2-catalyzed H3K36me3 bound to the Hif1a gene to modulate HIF-1α expression. Furthermore, Hif1a silencing suppressed Setd2 silencing-induced M1 macrophage polarization and glycolysis in RAW 264.7 cells. Moreover, overexpression of Setd2 inhibited CLP-induced lung injury and M1 macrophage polarization in mice. SETD2 suppressed M1 macrophage polarization and glycolysis via regulating HIF-1α through catalyzing H3K36me3 in sepsis.

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Data availability

The datasets used during this study are available from the corresponding author on reasonable request.

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Acknowledgements

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Funding

The present study was supported by the Natural Science Foundation of China (81801960, 82072220).

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Author notes

  1. Yan Meng and Kai-wen Kong contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care, Changhai Hospital, The Naval Medical University, 168 Changhai Road, Yangpu District, Shanghai, 200433, People’s Republic of China

    Yan Meng, Kai-wen Kong, Yong-qing Chang, Xiao-ming Deng & Tao Yang

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  1. Yan Meng
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  2. Kai-wen Kong
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  3. Yong-qing Chang
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Contributions

Y-M and KW-K performed the research and analyzed the data, YQ-C, Y-M and KW-K wrote the major part of the manuscript. T-Y and XM-D designed the research, ensured correct analysis of the data, and wrote the manuscript. All authors read approved the final manuscript. All authors critically revised the manuscript and gave final approval of the manuscript.

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Correspondence to Xiao-ming Deng or Tao Yang.

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Edited by Christian Bogdan.

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Supplementary Information

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430_2023_778_MOESM1_ESM.tif

Supplementary file1 Figure S1. Effect of Setd2 overexpression on M2 macrophage polarization in LPS-treated RAW 264.7 cells. (A, B) RAW 264.7 cells were transfected with Setd2 expression plasmid- or empty vector, and at 24 h after transfection, cells were treated with 2 μg/ml LPS for 24 h. Cells without treatment were used as a control. (C) Arg1 and (B) Il10 mRNA levels were assessed by RT-qPCR. Data are expressed as mean ± SD. n = 3. **P < 0.01, ***P < 0.001 vs. control. (TIF 91 KB)

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Meng, Y., Kong, Kw., Chang, Yq. et al. Histone methyltransferase SETD2 inhibits M1 macrophage polarization and glycolysis by suppressing HIF-1α in sepsis-induced acute lung injury. Med Microbiol Immunol 212, 369–379 (2023). https://doi.org/10.1007/s00430-023-00778-5

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  • DOI: https://doi.org/10.1007/s00430-023-00778-5

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