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α-Mangostin suppresses NLRP3 inflammasome activation via promoting autophagy in LPS-stimulated murine macrophages and protects against CLP-induced sepsis in mice

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Abstract

Background

The major mechanism of sepsis is immunosuppression caused by host response dysfunction. It has been found that α-Mangostin (α-M) is a potential candidate as a treatment for multiple inflammatory and immune disorders. To date, the role of α-M in host response during sepsis remains unexplored.

Methods and results

Herein, we examined the effect of α-M on macrophages-mediated host response in the presence of lipopolysaccharide (LPS), and the vital organ function, inflammatory response, and survival rate in septic mice. In murine peritoneal macrophages, α-M induced autophagy and then inhibited LPS-stimulated NLRP3 inflammasome activation, as well as interleukin-1β (IL-1β) production. Moreover, α-M improved phagocytosis and killing of macrophages, and increased M2 macrophages numbers after LPS stimulation. Furthermore, in vivo experiment suggested that α-M reduced serum levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-1β, alanine transaminase (ALT), aspartate transaminase (AST), and creatinine (Cr), whilst increased that of interleukin-10 (IL-10) in caecal ligation and puncture (CLP) mice.

Conclusion

Taken together, these findings showed that α-M-mediated macrophages autophagy contributed to NLRP3 inflammasome inactivation and α-M exerted organ protection in septic mice.

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References

  1. Shankar-Hari M, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis ans septic shock (sepsis-3). JAMA. 2016;315:775–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sartelli M, et al. Raising concerns about the sepsis-3 definitions. World J Emerg Surg. 2018;13:6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hotchkiss RS, et al. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Angus DC, Van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:840–51.

    Article  CAS  PubMed  Google Scholar 

  5. Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13:862–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Delano MJ, Ward PA. Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest. 2016;126:23–31.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cohen J, et al. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015;15:581–614.

    Article  PubMed  Google Scholar 

  8. Jensen IJ, Sjaastad FV, Griffith TS, Badovinac VP. Sepsis-induced T cell immunoparalysis: the ins and outs of impaired T cell immunity. J Immunol. 2018;200:1543–53.

    CAS  PubMed  Google Scholar 

  9. Savelkoel J, Claushuis TAM, vanEngelen TSR, Scheres LJJ, Wiersinga WJ. Global impact of World Sepsis Day on digital awareness of sepsis: an evaluation using Google Trends. Crit Care. 2018;22:61.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Anthony JL, Timothy RB, Matthew RR. Biology and metabolism of sepsis: innate immunity, bioenergetics, and autophagy. Surg Infect. 2016;17:286–93.

    Article  Google Scholar 

  11. Zhang L, Ai YH, Tsung A. Clinical application: restoration of immune homeostasis by autophagy as a potential therapeutic target in sepsis (review). Exp Ther Med. 2016;12:1159–67.

    Article  CAS  Google Scholar 

  12. Sridhar S, Botbol Y, Macian F, Cuervo AM. Autophagy and disease: always two sides to a problem. J pathol. 2012;226:255–73.

    Article  PubMed  Google Scholar 

  13. Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368:651–62.

    Article  CAS  PubMed  Google Scholar 

  14. Chen YQ, Klionsky DJ. The regulation of autophagy–unanswered questions. J Cell Sci. 2011;124:161–70.

    Article  CAS  PubMed  Google Scholar 

  15. Watanabe E, et al. Sepsis induces extensive autophagic vacuolization in hepatocytes: a clinical and laboratory-based study. Lab Invest. 2009;9:549–61.

    Article  Google Scholar 

  16. Ho J, et al. Autophagy in sepsis: degradation into exhaustion? Autophagy. 2016;12:1073–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen G, Li Y, Wang W, Deng L. Bioactivity and pharmacological properties of α-mangostin from the mangosteen fruit: a review. Expert Opin Ther Pat. 2018;3:1–13.

    Google Scholar 

  18. Scolamiero G, Pazzini C, Bonafè F, Guarnieri C, Muscari C. Effects of α-mangostin on viability, growth and cohesion of multicellular spheroids derived from human breast cancer cell lines. Int J Med Sci. 2018;15:23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu T, et al. Alpha-mangostin attenuates diabetic nephropathy in association with suppression of acid sphingomyelianse and endoplasmic reticulum stress. Biochem Biophys Res Commun. 2018;496:394–400.

    Article  CAS  PubMed  Google Scholar 

  20. Pan T, et al. Alpha-Mangostin suppresses interleukin-1β-induced apoptosis in rat chondrocytes by inhibiting the NF-κB signaling pathway and delays the progression of osteoarthritis in a rat model. Int Immunopharmacol. 2017;52:156–62.

    Article  CAS  PubMed  Google Scholar 

  21. Pimchan T, Maensiri D, Eumkeb G. Synergy and mechanism of action of α-mangostin and ceftazidime against ceftazidime-resistant Acinetobacter baumannii. Lett Appl Microbiol. 2017;65:285–91.

    Article  CAS  PubMed  Google Scholar 

  22. You BH, et al. α-Mangostin ameliorates dextran sulfate sodium-induced colitis through inhibition of NF-κB and MAPK pathways. Int Immunopharmacol. 2017;49:212–21.

    Article  CAS  PubMed  Google Scholar 

  23. Franceschelli S, et al. A novel biological role of α-mangostin in modulating inflammatory response through the activation of SIRT-1 signaling pathway. J Cell Physiol. 2016;231:2439–51.

    Article  CAS  PubMed  Google Scholar 

  24. Sivaranjani M, et al. In vitro activity of alpha-mangostin in killing and eradicating Staphylococcus epidermidis RP62A biofilms. Appl Microbiol Biotechnol. 2017;101:3349–59.

    Article  CAS  PubMed  Google Scholar 

  25. Chen ZL, et al. Transferrin-modified liposome promotes α-mangostin to penetrate the blood-brain barrier. Nanomedicine. 2016;12:421–30.

    Article  CAS  PubMed  Google Scholar 

  26. Catorce MN, et al. Alpha-mangostin attenuates brain inflammation induced by peripheral lipopolysaccharide administration in C57BL/6J mice. J Neuroimmunol. 2016;297:20–7.

    Article  CAS  Google Scholar 

  27. Patil NK, Bohannon JK, Sherwood ER. Immunotherapy: a promising approach to reverse sepsis-induced immunosuppression. Pharmacol Res. 2016;111:688–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yadav H, Cartin-Ceba R. Balance between hyperinflammation and immunosuppression in sepsis. Semin Respir Crit Care Med. 2016;37:42.

    Article  PubMed  Google Scholar 

  29. Fattahi F, Ward PA. Understanding immunosuppression after sepsis. Immunity. 2017;47:3.

    Article  CAS  PubMed  Google Scholar 

  30. Venet F, Rimmelé T, Monneret G. Management of sepsis-induced immunosuppression. Crit Care Clin. 2018;34:97.

    Article  PubMed  Google Scholar 

  31. Cavaillon JM, Adib-Conquy M. Monocytes/macrophages and sepsis. Crit Care Med. 2005;33(Suppl):S506–9.

    Article  PubMed  Google Scholar 

  32. Rabani R, et al. Mesenchymal stem cells enhance NOX2 dependent ROS production and bacterial killing in macrophages during sepsis. Eur Respir J. 2018;8:1702021.

    Article  CAS  Google Scholar 

  33. Liu Y, et al. Scutellarin Suppresses NLRP3 inflammasome activation in macrophages and protects mice against bacterial sepsis. Front Pharmacol. 2018;8:975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Xing L, et al. Role of M2 Macrophages in Sepsis-Induced Acute Kidney Injury. Shock. 2017;1:233–9.

    Google Scholar 

  35. Linch SN, Danielson ET, Kelly AM, Lee JJ, Gold JA. The effect of IL-5 on macrophages and PMNs in sepsis. Am J Resp Crit Care. 2009;179:A1024.

    Google Scholar 

  36. Lu XJ, et al. LECT2 protects mice against bacterial sepsis by activating macrophages via the CD209a receptor. J Exp Med. 2013;210:5–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang Y, et al. Alpha- mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates beta-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation. Neuropharmacology. 2012;62:871–81.

    Article  CAS  PubMed  Google Scholar 

  38. Jin L, Batra S, Jeyaseelan S. Deletion of Nlrp3 augments survival during polymicrobial sepsis by decreasing autophagy and enhancing phagocytosis. J Immunol. 2017;198:1253–62.

    Article  CAS  PubMed  Google Scholar 

  39. Long H, Xu B, Luo Y, Luo K. Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation. Am J Emerg Med. 2016;34:772–7.

    Article  PubMed  Google Scholar 

  40. Wu D, et al. Intermedin1-53 protects cardiac fibroblasts by inhibiting NLRP3 inflammasome activation during sepsis. Inflammation. 2018;41:505–14.

    Article  CAS  PubMed  Google Scholar 

  41. Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014;24:9–23.

    Article  CAS  PubMed  Google Scholar 

  42. Virgin HW, Levine B. Autophagy genes in immunity. Nat Immunol. 2009;10:461–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of General Intensive Care Unit, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310052, China

    Yun Ge, Xin Xu, Qiqiang Liang, Yongshan Xu & Man Huang

Authors
  1. Yun Ge
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  2. Xin Xu
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  3. Qiqiang Liang
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  4. Yongshan Xu
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  5. Man Huang
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Contributions

YG, MH guaranteed integrity of the entire study. YG designed the research, wrote the paper, analyzed the data. XX, QL,YX conducted experiments. MH contributed to revise the paper. All authors critically reviewed the manuscript for important intellectual content and approved the final version.

Corresponding author

Correspondence to Man Huang.

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Responsible Editor: John Di Battista.

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Ge, Y., Xu, X., Liang, Q. et al. α-Mangostin suppresses NLRP3 inflammasome activation via promoting autophagy in LPS-stimulated murine macrophages and protects against CLP-induced sepsis in mice. Inflamm. Res. 68, 471–479 (2019). https://doi.org/10.1007/s00011-019-01232-0

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  • DOI: https://doi.org/10.1007/s00011-019-01232-0

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