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Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration

Acta Pharmacologica Sinica volume 44, pages 1404–1415 (2023)Cite this article

Abstract

Myokines, which are recently identified cytokines secreted by skeletal muscle in response to stimulation, are crucial for the maintenance of liver function. Fulminant hepatitis (FH) is a life-threatening pathological condition with severe hepatic dysfunction. In this study, we investigated the role of meteorin-like (METRNL), a new myokine, in the pathogenesis of FH. We compared serum samples and liver tissues from FH patients and healthy controls and found that hepatic and serum METRNL levels were significantly increased in FH patients, and serum METRNL levels were related to disease severity in FH patients. We then established a concanavalin A-induced FH model in METRNL-overexpressing and control mice. We found that hepatic METRNL levels in FH mice were significantly increased, and METRNL in the liver was mainly derived from macrophages. In the cultured mouse macrophage line (RAW264.7 cells) and mouse primary peritoneal macrophages (PMs), METRNL overexpression significantly inhibited the release of the proinflammatory cytokines TNF and IL-1β. In METRNL-overexpressing mice, concanavalin A-induced liver injury was significantly ameliorated. Moreover, METRNL overexpression significantly reduced chemokine-dependent inflammatory cell infiltration into the liver. METRNL overexpression also suppressed liver CD4+ T cell differentiation into Th 1 cells and inhibited the secretion of Th 1 cytokines. Taken together, these data suggest that METRNL overexpression effectively ameliorates FH. Therefore, METRNL may serve as a potential biomarker and therapeutic target for FH.

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Fig. 1: The increase in METRNL expression in the FH mouse model was derived from macrophages.
Fig. 2: METRNL inhibited the secretion of proinflammatory factors by macrophages.
Fig. 3: METRNL overexpression alleviated FH in vivo.
Fig. 4: Macrophage-derived METRNL attenuated liver injury by inhibiting immune cell infiltration.
Fig. 5: Macrophage-derived METRNL attenuated liver inflammation by suppressing Th1 cells.
Fig. 6: METRNL-mediated suppression of liver inflammation was chemokine‑dependent.
Fig. 7: Serum and hepatic METRNL levels were upregulated in FH patients.

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Data availability

The dataset (excluding personal identifiers) will be available to proper academic parties upon request from the corresponding author in accordance with the data sharing policies of Shanghai Jiao Tong University School of Medicine.

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Acknowledgements

This study was funded by the Natural Science Foundation of Shanghai (20ZR1433500), the Major Project of National Thirteenth Five-year Plan (2017ZX09304016), and the National Natural Science Foundation of China (8210030899).

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  1. These authors contributed equally: Ya-nan Du, Jia-ming Teng

Authors and Affiliations

  1. Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Ya-nan Du, Jia-ming Teng, Tian-hui Zhou, Bing-ying Du & Wei Cai

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Contributions

YND performed the experiments and wrote the manuscript. JMT and BYD made the clinical diagnoses and collected the clinical samples. THZ performed the data analysis. WC designed and supervised the project and revised the manuscript for important content.

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Correspondence to Bing-ying Du or Wei Cai.

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The authors declare no competing interests.

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Written consent was obtained from each subject.

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The study was approved by the Human Ethics Committee, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.

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Du, Yn., Teng, Jm., Zhou, Th. et al. Meteorin-like protein overexpression ameliorates fulminant hepatitis in mice by inhibiting chemokine-dependent immune cell infiltration. Acta Pharmacol Sin 44, 1404–1415 (2023). https://doi.org/10.1038/s41401-022-01049-4

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