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

He, Xue-ling1,2,3,4; Chen, Jia-yun1,2,3,4; Feng, Yu-lin5; Song, Ping6; Wong, Yin Kwan7; Xie, Lu-lin3,4; Wang, Chen1,2; Zhang, Qian1,2,9; Bai, Yun-meng3,4; Gao, Peng1,2; Luo, Piao1,2; Liu, Qiang8; Liao, Fu-long1,2; Li, Zhi-jie3,4; Jiang, Yong10; Wang, Ji-gang1,2,3,4,5

2023-04-01

10.1038/s41401-023-01065-y

ACTA PHARMACOLOGICA SINICA   Impact Factor & Quartile

1671-4083

1745-7254

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.

sepsis scRNA-seq artesunate liver hepatic endothelial cells macrophages lymphocytes neutrophils

SCI

English

Corresponding

Establishment of Sino-Austria "Belt and Road" Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research[2020YFE0205100] ; National Key Research and Development Program of China["2020YFA0908000","2022YFC2303600"] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002] ; National Natural Science Foundation of China["82141001","82274182","82074098","82173914"] ; CACMS Innovation Fund["CI2021A05101","CI2021A05104"] ; Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences[CI2021B014] ; Science and Technology Foundation of Shenzhen[JCYJ20210324115800001] ; 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","ZZ15-ND-10"] ; Shenzhen Governmental Sustainable Development Fund[KCXFZ20201221173612034] ; Shenzhen Key Laboratory of Kidney Diseases[ZDSYS201504301616234] ; Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties[SZGSP001]

Chemistry ; Pharmacology & Pharmacy

Chemistry, Multidisciplinary ; Pharmacology & Pharmacy

WOS:000969020000001

NATURE PUBL GROUP

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.China Acad Chinese Med Sci, Artemisinin Res Ctr, Beijing 100700, Peoples R China
2.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Dept Nephrol,Shenzhen Key Lab Kidney Dis, Shenzhen 518020, Peoples R China
4.Southern Univ Sci & Technol, Shenzhen Peoples Hosp, Affiliated Hosp 1, Shenzhen Clin Res Ctr Geriatr, Shenzhen 518020, Peoples R China
5.Jiangxi Univ Chinese Med, Natl Pharmaceut Engn Ctr Solid Preparat Chinese He, Nanchang 330004, Peoples R China
6.China Acad Chinese Med Sci, Beijing 100700, Peoples R China
7.Natl Univ Singapore, Dept Biol Sci, Singapore 117543, Singapore
8.Stanford Univ, Sch Med, Adv Drug Delivery & Regenerat Biomat Lab, Stanford, CA 94304 USA
9.Stanford Univ, Sch Med, Cardiovasc Pharmacol Div Cardiovasc Inst, Stanford, CA 94304 USA
10.Southern Med Univ, Sch Basic Med Sci, Guangdong Prov Key Lab Prote, Guangzhou 510515, Peoples R China

He, Xue-ling,Chen, Jia-yun,Feng, Yu-lin,et al. Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate[J]. ACTA PHARMACOLOGICA SINICA,2023.

He, Xue-ling.,Chen, Jia-yun.,Feng, Yu-lin.,Song, Ping.,Wong, Yin Kwan.,...&Wang, Ji-gang.(2023).Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate.ACTA PHARMACOLOGICA SINICA.

He, Xue-ling,et al."Single-cell RNA sequencing deciphers the mechanism of sepsis-induced liver injury and the therapeutic effects of artesunate".ACTA PHARMACOLOGICA SINICA (2023).