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Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate

Acta Pharmacologica Sinica volume 44, pages 1801–1814 (2023)Cite this article

Abstract

Liver, as an immune and detoxification organ, represents an important line of defense against bacteria and infection and a vulnerable organ that is easily injured during sepsis. Artesunate (ART) is an anti-malaria agent, that also exhibits broad pharmacological activities including anti-inflammatory, immune-regulation and liver protection. In this study, we investigated the cellular responses in liver to sepsis infection and ART hepatic-protective mechanisms against sepsis. Cecal ligation and puncture (CLP)-induced sepsis model was established in mice. The mice were administered ART (10 mg/kg, i.p.) at 4 h, and sacrificed at 12 h after the surgery. Liver samples were collected for preparing single-cell RNA transcriptome sequencing (scRNA-seq). The scRNA-seq analysis revealed that sepsis-induced a dramatic reduction of hepatic endothelial cells, especially the subtypes characterized with proliferation and differentiation. Macrophages were recruited during sepsis and released inflammatory cytokines (Tnf, Il1b, Il6), chemokines (Ccl6, Cd14), and transcription factor (Nfkb1), resulting in liver inflammatory responses. Massive apoptosis of lymphocytes and abnormal recruitment of neutrophils caused immune dysfunction. ART treatment significantly improved the survival of CLP mice within 96 h, and partially relieved or reversed the above-mentioned pathological features, mitigating the impact of sepsis on liver injury, inflammation, and dysfunction. This study provides comprehensive fundamental proof for the liver protective efficacy of ART against sepsis infection, which would potentially contribute to its clinical translation for sepsis therapy.

Single cell transcriptome reveals the changes of various hepatocyte subtypes of CLP-induced liver injury and the potential pharmacological effects of artesunate on sepsis.

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Acknowledgements

We gratefully acknowledge financial support from the Establishment of Sino-Austria “Belt and Road” Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research (2020YFE0205100); the National Key Research and Development Program of China (2020YFA0908000 and 2022YFC2303600); the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-C-202002); the National Natural Science Foundation of China (82141001, 82274182, 82074098 and 82173914); the CACMS Innovation Fund (CI2021A05101 and CI2021A05104); the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (CI2021B014); the Science and Technology Foundation of Shenzhen (JCYJ20210324115800001); the Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ14-YQ-050, ZZ14-YQ-051, ZZ14-YQ-052, ZZ14-FL-002, ZZ14-ND-010 and ZZ15-ND-10); the Shenzhen Governmental Sustainable Development Fund (KCXFZ20201221173612034); the Shenzhen Key Laboratory of Kidney Diseases (ZDSYS201504301616234); the Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP001).

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  1. These authors contributed equally: Xue-ling He, Jia-yun Chen, Yu-lin Feng, Ping Song.

Authors and Affiliations

  1. Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Xue-ling He, Jia-yun Chen, Chen Wang, Qian Zhang, Peng Gao, Piao Luo, Fu-long Liao & Ji-gang Wang

  2. Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, and Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People’s Hospital, the First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, China

    Xue-ling He, Jia-yun Chen, Lu-lin Xie, Yun-meng Bai, Zhi-jie Li & Ji-gang Wang

  3. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330004, China

    Yu-lin Feng & Ji-gang Wang

  4. China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Ping Song

  5. Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore

    Yin Kwan Wong

  6. Advanced Drug Delivery and Regenerative Biomaterials Laboratory, and Cardiovascular Pharmacology Division of Cardiovascular Institute, School of Medicine, Stanford University, Stanford, CA, 94304, USA

    Qiang Liu

  7. Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Yong Jiang

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Contributions

JGW, YJ, and ZJL conceived and designed the experiments. XLH, JYC, YLF, and PS performed the major experiment and main data analysis. LLX, QZ, PG, and PL assisted with animal experiments and tissue dissociation. YKW, CW, YMB, and QL executed other experiments and bioinformatic analyses. XLH, JYC, and YKW wrote the manuscript. FLL and ZJL revised the manuscript. All authors have reviewed and edited the manuscript and agreed with the content of the manuscript.

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Correspondence to Zhi-jie Li, Yong Jiang or Ji-gang Wang.

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He, Xl., Chen, Jy., Feng, Yl. et al. Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate. Acta Pharmacol Sin 44, 1801–1814 (2023). https://doi.org/10.1038/s41401-023-01065-y

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