Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis

Jiayun Chen; Xueling He; Yunmeng Bai; Jing Liu; Yin Kwan Wong; Lulin Xie; Qian Zhang; Piao Luo; Peng Gao; Liwei Gu; Qiuyan Guo; Guangqing Cheng; Chen Wang; Jigang Wang

doi:10.1016/j.jpha.2023.02.006

Volume 13 Issue 7

Jul. 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(7): 817-829

Jiayun Chen, Xueling He, Yunmeng Bai, Jing Liu, Yin Kwan Wong, Lulin Xie, Qian Zhang, Piao Luo, Peng Gao, Liwei Gu, Qiuyan Guo, Guangqing Cheng, Chen Wang, Jigang Wang. Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 817-829. doi: 10.1016/j.jpha.2023.02.006

Citation:

Jiayun Chen, Xueling He, Yunmeng Bai, Jing Liu, Yin Kwan Wong, Lulin Xie, Qian Zhang, Piao Luo, Peng Gao, Liwei Gu, Qiuyan Guo, Guangqing Cheng, Chen Wang, Jigang Wang. Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 817-829. doi: 10.1016/j.jpha.2023.02.006

Citation:

Jiayun Chen, Xueling He, Yunmeng Bai, Jing Liu, Yin Kwan Wong, Lulin Xie, Qian Zhang, Piao Luo, Peng Gao, Liwei Gu, Qiuyan Guo, Guangqing Cheng, Chen Wang, Jigang Wang. Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis[J]. Journal of Pharmaceutical Analysis, 2023, 13(7): 817-829. doi: 10.1016/j.jpha.2023.02.006

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Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis

doi: 10.1016/j.jpha.2023.02.006

a. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China;
b. 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, Guangdong, 518020, China;
c. Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 518020, China

Funds:

The authors gratefully acknowledge the financial support by the Establishment of Sino-Austria “Belt and Road” Joint Laboratory on Traditional Chinese Medicine for Severe Infectious Diseases and Joint Research, China (Grant No.: 2020YFE0205100), the National Key Research and Development Program of China (Grant Nos.: 2020YFA0908000 and 2022YFC2303600), the Distinguished Expert Project of Sichuan Province Tianfu Scholar (Grant No.: CW202002), the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine, China (Grant No.: ZYYCXTD-C-202002), the National Natural Science Foundation of China (Grant Nos.: 82141001, 82274182, 82074098, and 82173914), the China Academy of Chinese Medical Sciences (CACMS) Innovation Fund, China (Grant Nos.: CI2021A05101 and CI2021A05104), the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (Grant No.: CI2021B014), the Science and Technology Foundation of Shenzhen, China (Grant No.: JCYJ20210324115800001), the Science and Technology Foundation of Shenzhen, China (Shenzhen Clinical Medical Research Center for Geriatric Diseases), the National Key R&D Program of China Key Projects for International Cooperation on Science, Technology and Innovation (Grant No.: 2020YFE0205100), the Fundamental Research Funds for the Central Public Welfare Research Institutes, China (Grant Nos.: ZZ14-YQ-050, ZZ14-YQ-051, ZZ14-YQ-052, ZZ14-FL-002, ZZ14-ND-010, and ZZ15-ND-10), Shenzhen Governmental Sustainable Development Fund, China (Grant No.: KCXFZ20201221173612034), Shenzhen key Laboratory of Kidney Diseases, China (Grant No.: ZDSYS201504301616234), and Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties, China (Grant No.: SZGSP001).

Received Date: Oct. 30, 2022
Accepted Date: Feb. 16, 2023
Rev Recd Date: Feb. 08, 2023
Available Online: Aug. 05, 2023
Publish Date: Feb. 24, 2023

Abstract

Abstract

Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction. Studies on the therapeutic effect and mechanism of immunomodulatory drugs on the sepsis-induced hyperinflammatory or immunosuppression states of various immune cells remain limited. This study aimed to investigate the protective effects and underlying mechanism of artesunate (ART) on the splenic microenvironment of cecal ligation and puncture-induced sepsis model mice using single-cell RNA sequencing (scRNA-seq) and experimental validations. The scRNA-seq analysis revealed that ART inhibited the activation of pro-inflammatory macrophages recruited during sepsis. ART could restore neutrophils’ chemotaxis and immune function in the septic spleen. It inhibited the activation of T regulatory cells but promoted the cytotoxic function of natural killer cells during sepsis. ART also promoted the differentiation and activity of splenic B cells in mice with sepsis. These results indicated that ART could alleviate the inflammatory and/or immunosuppressive states of various immune cells involved in sepsis to balance the immune homeostasis within the host. Overall, this study provided a comprehensive investigation of the regulatory effect of ART on the splenic microenvironment in sepsis, thus contributing to the application of ART as adjunctive therapy for the clinical treatment of sepsis.
- Artesunate,
- Sepsis,
- Single-cell RNA sequencing,
- Immunomodulatory activity

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References(40)

References

M. Singer, C.S. Deutschman, C.W. Seymour, et al., The third international consensus definitions for sepsis and septic shock (sepsis-3), JAMA 315 (2016) 801-810.

T. van der Poll, M. Shankar-Hari, W.J. Wiersinga, The immunology of sepsis, Immunity 54 (2021) 2450-2464.

R.S. Hotchkiss, G. Monneret, D. Payen, Sepsis-induced immunosuppression: From cellular dysfunctions to immunotherapy, Nat. Rev. Immunol. 13 (2013) 862-874.

T. van der Poll, F.L. van de Veerdonk, B.P. Scicluna, et al., The immunopathology of sepsis and potential therapeutic targets, Nat. Rev. Immunol. 17 (2017) 407-420.

S.M. Lewis, A. Williams, S.C. Eisenbarth, Structure and function of the immune system in the spleen, Sci. Immunol. 4 (2019), eaau6085.

M. Altamura, L. Caradonna, L. Amati, et al., Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance, Immunopharmacol. Immunotoxicol. 23 (2001) 153-161.

X. Mu, C. Wang, Artemisinins-a promising new treatment for systemic lupus erythematosus: A descriptive review, Curr. Rheumatol. Rep. 20 (2018), 55.

L. Hou, H. Huang, Immune suppressive properties of artemisinin family drugs, Pharmacol. Ther. 166 (2016) 123-127.

X. Tong, L. Chen, S.-J. He, et al., Artemisinin derivative SM934 in the treatment of autoimmune and inflammatory diseases: Therapeutic effects and molecular mechanisms, Acta. Pharmacol. Sin. 43 (2022) 3055-3061.

T. Zhang, Y. Zhang, N. Jiang, et al., Dihydroartemisinin regulates the immune system by promotion of CD8⁺ T lymphocytes and suppression of B cell responses, Sci. China Life Sci. 63 (2020) 737-749.

T.-H. Cao, S.-G. Jin, D.-S. Fei, et al., Artesunate protects against sepsis-induced lung injury via heme oxygenase-1 modulation, Inflammation 39 (2016) 651-662.

E. Zhang, J. Wang, Q. Chen, et al., Artesunate ameliorates sepsis-induced acute lung injury by activating the mTOR/AKT/PI3K axis, Gene 759 (2020), 144969.

S.-P. Lin, J.-X. Wei, J.-S. Hu, et al., Artemisinin improves neurocognitive deficits associated with sepsis by activating the AMPK axis in microglia, Acta Pharmacol. Sin. 42 (2021) 1069-1079.

E. Hedlund, Q. Deng, Single-cell RNA sequencing: Technical advancements and biological applications, Mol. Aspects Med. 59 (2018) 36-46.

M. Wen, G. Cai, J. Ye, et al., Single-cell transcriptomics reveals the alteration of peripheral blood mononuclear cells driven by sepsis, Ann. Transl. Med. 8 (2020), 125.

T. Wang, X. Zhang, Z. Liu, et al., Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia, Genomics 113 (2021) 1219-1233.

R.-Q. Yao, Z.-X. Li, L.-X. Wang, et al., Single-cell transcriptome profiling of the immune space-time landscape reveals dendritic cell regulatory program in polymicrobial sepsis, Theranostics 12 (2022) 4606-4628.

F.V. Sjaastad, I.J. Jensen, R.R. Berton, et al., Inducing experimental polymicrobial sepsis by cecal ligation and puncture, Curr. Protoc. Immunol. 131 (2020), e110.

S. Chen, Y. Zhou, Y. Chen, et al., fastp: An ultra-fast all-in-one FASTQ preprocessor, Bioinformatics 34 (2018) i884-i890.

T. Stuart, A. Butler, P. Hoffman, et al., Comprehensive integration of single-cell data, Cell 177 (2019) 1888-1902.e21.

C. Trapnell, D. Cacchiarelli, J. Grimsby, et al., The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells, Nat. Biotechnol. 32 (2014) 381-386.

S. Jin, C.F. Guerrero-Juarez, L. Zhang, et al., Inference and analysis of cell-cell communication using CellChat, Nat. Commun. 12 (2021), 1088.

G.Y. Song, C.S. Chung, I.H. Chaudry, et al., IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis, Surgery 128 (2000) 133-138.

G.D. Gregory, S.S. Raju, S. Winandy, et al., Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE, J. Clin. Invest. 116 (2006) 1327-1336.

X. Qi, Y. Yu, R. Sun, et al., Identification and characterization of neutrophil heterogeneity in sepsis, Crit. Care 25 (2021), 50.

I.J. Jensen, F.V. Sjaastad, T.S. Griffith, et al., Sepsis-Induced T Cell Immunoparalysis: The ins and outs of impaired T cell immunity, J. Immunol. 200 (2018) 1543-1553.

V. Atsaves, V. Leventaki, G.Z. Rassidakis, et al., AP-1 transcription factors as regulators of immune responses in cancer, Cancers (Basel) 11 (2019), 1037.

C.A. Dinarello, Proinflammatory cytokines, Chest 118 (2000) 503-508.

M.J. Delano, P.A. Ward, Sepsis-induced immune dysfunction: Can immune therapies reduce mortality? J. Clin. Invest. 126 (2016) 23-31.

D.B. Darden, X. Dong, M.A. Brusko, et al., A novel single cell RNA-seq analysis of non-myeloid circulating cells in late sepsis, Front. Immunol. 12 (2021), 696536.

X.-J. Wang, J. Zhuo, G.-H. Luo, et al., Androgen deprivation accelerates the prostatic urethra wound healing after thulium laser resection of the prostate by promoting re-epithelialization and regulating the macrophage polarization, Prostate 77(2017) 708-717.

B.-Y. Yang, G.-Y. Deng, R.-Z. Zhao, et al., Porous Se@SiO₂ nanosphere-coated catheter accelerates prostatic urethra wound healing by modulating macrophage polarization through reactive oxygen species-NF-κB pathway inhibition, Acta Biomater. 88 (2019) 392-405.

S.F. Liu, A.B. Malik, NF-κB activation as a pathological mechanism of septic shock and inflammation, Am. J. Physiol. Lung Cell. Mol. Physiol. 290 (2006) L622-L645.

P.H.C. Leliefeld, C.M. Wessels, L.P.H. Leenen, et al., The role of neutrophils in immune dysfunction during severe inflammation, Crit. Care 20 (2016), 73.

C.C. Gray, B. Biron-Girard, M.E. Wakeley, et al., Negative Immune Checkpoint Protein, VISTA, Regulates the CD4⁺ T_reg Population During Sepsis Progression to Promote Acute Sepsis Recovery and Survival, Front. Immunol. 13 (2022), 861670.

F. Venet, C.-S. Chung, G. Monneret, et al., Regulatory T cell populations in sepsis and trauma, J. Leukoc. Biol. 83 (2008) 523-535.

E.Y. Kim, H. Ner-Gaon, J. Varon, et al., Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN_-γ in NK cells, J. Clin. Invest. 130 (2020) 3238-3252.

B.G. Chousterman, F.K. Swirski, Innate response activator B cells: Origins and functions, Int. Immunol. 27 (2015) 537-541.

P. Luo, Q. Zhang, T.-Y. Zhong, et al., Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect, Mil. Med. Res. 9 (2022), 22.

Q. Zhang, P. Luo, F. Xia, et al., Capsaicin ameliorates inflammation in a TRPV1-independent mechanism by inhibiting PKM2-LDHA-mediated Warburg effect in sepsis, Cell Chem. Biol. 29 (2022) 1248-1259.e6.

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