Swertianolin ameliorates immune dysfunction in sepsis via blocking the immunosuppressive function of myeloid-derived suppressor cells



  • Zongfang Ren The First School of Clinical Medicine, Southern Medical University, Guangzhou, China. https://orcid.org/0000-0002-7804-1510
  • Haoren Tang Department of Gastroenterological Surgery, the Second Affiliated Hospital of Kunming Medical University, Kunming , China.
  • Linjun Wan Department of Critical Care Medicine, the Second Affiliated Hospital of Kunming Medical University, Kunming , China.
  • Xing Liu Graduate School of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • Ning Tang Department of Neurology, The First People's Hospital of Yunnan Province, Kunming University of Science and Technology, Kunming, China.
  • Lingling Wang Department of Medical Intensive Care Unit, General Hospital of Southern Theater Command of PLA, Guangzhou , China.
  • Zhenhui Guo | micugzh@vip.sina.com The First School of Clinical Medicine, Southern Medical University, Guangzhou, China. https://orcid.org/0000-0001-9254-626X


In this study, we studied the long-term proliferation trajectory of myeloid-derived suppressor cells (MDSCs) in murine sepsis model and investigated whether swertianolin could modulate the immunosuppressive function of MDSCs. A murine sepsis model was established by cecal ligation and perforation (CLP), according to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. The bone marrow and spleen of the mice were collected at 24 h, 72 h, 7 and 15 d after sepsis induction. The proportions of monocytic-MDSCs (M-MDSCs; CD11b+LY6G-LY6Chi) and granulocytic-MDSCs (G-MDSC, CD11b+ Ly6G+ Ly6Clow) were analyzed by flow cytometry. Then, we have investigated whether swertianolin could modulate the immunosuppressive function of MDSCs in in vitro experiments. G-MDSCs and M-MDSCs increased acutely after sepsis with high levels sustained over a long period of time. G-MDSCs were the main subtype identified in the murine model of sepsis with polymicrobial peritonitis. Furthermore, it was found that swertianolin reduced significantly interleukin-10 (IL-10), nitric oxide (NO), reactive oxygen species (ROS), and arginase production in MDSCs, while reducing MDSC proliferation and promoting MDSC differentiation into dendritic cells. Swertianolin also improved T-cell activity by blocking the immunosuppressive effect of MDSCs. Both subsets of MDSCs significantly increased in the bone marrow and spleen of the mice with sepsis, with G-MDSCs being the main subtype identified. Swertianolin effectively regulated the functions of MDSCs and reduced immune suppression.



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Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:775-87. DOI: https://doi.org/10.1001/jama.2016.0289

Lewis AJ, Rosengart MR. Bench-to-bedside: A translational perspective on murine models of sepsis. Surg Infect (Larchmt) 2018;19:137-41. DOI: https://doi.org/10.1089/sur.2017.308

Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011;306:2594-605. DOI: https://doi.org/10.1001/jama.2011.1829

Rosenthal MD. Persistent inflammatory, immunosuppressed, catabolic syndrome (PICS): A new phenotype of multiple organ failure. J Adv Nutr Hum Metab 2015;1:e784.

McPeak MB, Youssef D, Williams DA, Pritchett CL, Yao ZQ, McCall CE, et al. Frontline Science: Myeloid cell-specific deletion of Cebpb decreases sepsis-induced immunosuppression in mice. J Leukoc Biol 2017;102:191-200. DOI: https://doi.org/10.1189/jlb.4HI1216-537R

Hotchkiss RSD, Monneret GP, Payen DM. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013;13:260-8. DOI: https://doi.org/10.1016/S1473-3099(13)70001-X

Bosurgi R. Sepsis: a need for new solutions. Lancet Infect Dis 2015;15:498-99. DOI: https://doi.org/10.1016/S1473-3099(15)70030-7

Arens C, Bajwa SA, Koch C, Siegler BH, Schneck E, Hecker A, et al. Sepsis-induced long-term immune paralysis-results of a descriptive, explorative study. Crit Care 2016;20:93-9. DOI: https://doi.org/10.1186/s13054-016-1233-5

Fleming V, Hu X, Weber R, Nagibin V, Groth C, Altevogt P, et al. Targeting myeloid-derived suppressor cells to bypass tumor-induced immunosuppression. Front Immunol 2018;9:398. DOI: https://doi.org/10.3389/fimmu.2018.00398

Brudecki L, Ferguson DA, Yin D, Lesage GD, McCall CE, El Gazzar M. Hematopoietic Stem-progenitor cells restore immunoreactivity and improve survival in late sepsis. Infect Immun 2012;80:602-11.

Nagaraj S, Gabrilovich DI. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-74.

Zeng Q, Yang B, Sun H, Feng G, Jin L, Zou Z, et al. Myeloid-derived suppressor cells are associated with viral persistence and downregulation of TCR ζ chain expression on CD8+ T cells in chronic hepatitis C patients. Mol Cells 2014;37:66-73. DOI: https://doi.org/10.14348/molcells.2014.2282

Movahedi K, Guilliams M, Van den Bossche J, Van den Bergh R, Gysemans C, Beschin A, et al. Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 2008;111:4233-44. DOI: https://doi.org/10.1182/blood-2007-07-099226

Uhel F, Azzaoui I, Gregoire M, Pangault C, Dulong J, Tadie JM, et al. Early expansion of circulating granulocytic myeloid-derived suppressor cells predicts development of nosocomial infections in patients with sepsis. Am J Respir Crit Care Med 2017;196:315-27. DOI: https://doi.org/10.1164/rccm.201606-1143OC

Nagaraj S, Youn J, Weber H, Iclozan C, Lu L, Cotter MJ, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res 2010;16:1812-23. DOI: https://doi.org/10.1158/1078-0432.CCR-09-3272

Qu P, Wang L, Lin PC. Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Lett 2015;380:253-6. DOI: https://doi.org/10.1016/j.canlet.2015.10.022

Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol 2018;19:108-19. DOI: https://doi.org/10.1038/s41590-017-0022-x

Wu X, Gu Y, Li L. The anti-hyperplasia, anti-oxidative and anti-inflammatory properties of Qing Ye Dan and swertiamarin in testosterone-induced benign prostatic hyperplasia in rats. Toxicol Lett 2017;265:9-16. DOI: https://doi.org/10.1016/j.toxlet.2016.11.011

Zhang L, Cheng Y, Du X, Chen S, Feng X, Gao Y, et al. Swertianlarin, an herbal agent derived from Swertia mussotii Franch, attenuates liver injury, inflammation, and cholestasis in common bile duct-ligated rats. Evid Based Complement Alternat Med 2015;2015:948376. DOI: https://doi.org/10.1155/2015/948376

Tang H, Ke Y, Ren Z, Lei X, Xiao S, Bao T, et al. Bioinformatics analysis of differentially expressed genes in hepatocellular carcinoma cells exposed to Swertiamarin. J Cancer 2019;10:6526-34. DOI: https://doi.org/10.7150/jca.33666

He J, Tian C, Ouyang H, Adelakun TA, Yu B, Chang Y, et al. Determination of swertianolin in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. Biomed Chromatogr 2014;28:1418-22. DOI: https://doi.org/10.1002/bmc.3184

Tian C, Zhang T, Wang L, Shan Q, Jiang L. The hepatoprotective effect and chemical constituents of total iridoids and xanthones extracted from Swertia mussotii Franch. J Ethnopharmacol 2014;154:259-66. DOI: https://doi.org/10.1016/j.jep.2014.04.018

Wani BA, Ramamoorthy D, Rather MA, Arumugam N, Qazi AK, Majeed R, et al. Induction of apoptosis in human pancreatic MiaPaCa-2 cells through the loss of mitochondrial membrane potential (DeltaPsim) by Gentiana kurroo root extract and LC-ESI-MS analysis of its principal constituents. Phytomedicine 2013;20:723-33. DOI: https://doi.org/10.1016/j.phymed.2013.01.011

Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-74. DOI: https://doi.org/10.1038/nri2506

Bronte V. Myeloid-derived suppressor cells in inflammation: Uncovering cell subsets with enhanced immunosuppressive functions. Eur J Immunol 2009;39:2670-2. DOI: https://doi.org/10.1002/eji.200939892

Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2010;32:19-25. DOI: https://doi.org/10.1016/j.it.2010.10.002

Cao T, Geng C, Ma Y, He K, Zhou N, Zhou J, et al. Chemical constituents of Swertia delavayi and their anti-hepatitis B virus activity. Zhongguo Zhong Yao Za Zhi 2015;40:897-902.

Hotchkiss RS, Moldawer LL, Phimister EG. Parallels between cancer and infectious disease. N Engl J Med 2014;371:380-3. DOI: https://doi.org/10.1056/NEJMcibr1404664

Ward PA, Rittirsch D, Flierl MA, Huber-Lang MS. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 2008;4:31-6. DOI: https://doi.org/10.1038/nprot.2008.214

Nascimento DC, Melo PH, Piñeros AR, Ferreira RG, Colón DF, Donate PB, et al. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population. Nat Commun 2017;8:389-95. DOI: https://doi.org/10.1038/ncomms14919

Janols H, Bergenfelz C, Allaoui R, Larsson A, Rydén L, Björnsson S, et al. A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases. J Leukoc Biol 2014;96:685-93. DOI: https://doi.org/10.1189/jlb.5HI0214-074R

Richard S. Hotchkiss MD. The pathophysiology and treatment of sepsis. N Engl J Med 2003;11:273-8.

Riviello ED, Sugira V, Twagirumugabe T. Sepsis research and the poorest of the poor. Lanvet Infect Dis 2015;15:501-3. DOI: https://doi.org/10.1016/S1473-3099(15)70148-9

Rosenthal MD, Moore FA. Persistent inflammation, immunosuppression, and catabolism: Evolution of multiple organ dysfunction. Surg Infect 2016;17:167-72. DOI: https://doi.org/10.1089/sur.2015.184

Benjamim CF. Reversal of long-term sepsis-induced immunosuppression by dendritic cells. Blood 2005;1:127-31. DOI: https://doi.org/10.1182/blood-2004-08-3251

Deutschman CS, Tracey KJ. Sepsis: Current dogma and new perspectives. Immunity 2014;40:463-75. DOI: https://doi.org/10.1016/j.immuni.2014.04.001

Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 2016;126:23-31. DOI: https://doi.org/10.1172/JCI82224

Shao R, Fang Y, Yu H, Zhao L, Jiang Z, Li CS. Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients: a prospective cohort study. Crit Care 2016;20:124. DOI: https://doi.org/10.1186/s13054-016-1301-x

Goodwin AJ, Rice DA, Simpson KN, Ford DW. Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med 2015;43:738-46. DOI: https://doi.org/10.1097/CCM.0000000000000859

Lv R, Zhao J, Lei M, Xiao D, Yu Y, Xie J. IL-33 Attenuates sepsis by inhibiting IL-17 receptor signaling through upregulation of SOCS3. Cell Physiol Biochem 2017;42:1961-72. DOI: https://doi.org/10.1159/000479836

Mira JC, Gentile LF, Mathias BJ, Efron PA, Brakenridge SC, Mohr AM, et al. Sepsis pathophysiology, chronic critical illness, and persistent inflammation-immunosuppression and catabolism syndrome. Crit Care Med 2017;45:253-62. DOI: https://doi.org/10.1097/CCM.0000000000002074

Brudecki L, Ferguson DA, Yin D, Lesage GD, McCall CE, El Gazzar M. Hematopoietic stem-progenitor cells restore immunoreactivity and improve survival in late sepsis. Infect Immun 2012;80:602-11. DOI: https://doi.org/10.1128/IAI.05480-11


Sepsis, myeloid-derived suppressor cells, immunosuppression, swertianolin
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How to Cite
Ren, Z., Tang, H., Wan, L., Liu, X., Tang, N., Wang, L., & Guo, Z. (2021). Swertianolin ameliorates immune dysfunction in sepsis <em>via</em> blocking the immunosuppressive function of myeloid-derived suppressor cells . European Journal of Histochemistry, 65(3). https://doi.org/10.4081/ejh.2021.3292

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