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IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation

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Abstract

Objective and design

The aim of this study was to investigate the contribution of IL-33/ST2 axis in the onset and progression of acute liver injury using a mice model of drug-induced liver injury (DILI).

Material and treatments

DILI was induced by overdose administration of acetaminophen (APAP) by oral gavage in wild-type BALB/c, ST2-deficient mice and in different bone marrow chimeras. Neutrophils were depleted by anti-Ly6G and macrophages with clodronate liposomes (CLL).

Methods

Blood and liver were collected for biochemical, immunologic and genetic analyses. Mice were imaged by confocal intravital microscopy and liver non-parenchymal cells and hepatocytes were isolated for flow cytometry, genetic and immunofluorescence studies.

Results

Acetaminophen overdose caused a massive necrosis and accumulation of immune cells within the liver, concomitantly with IL-33 and chemokine release. Liver non-parenchymal cells were the major sensors for IL-33, and amongst them, neutrophils were the major players in amplification of the inflammatory response triggered by IL-33/ST2 signalling pathway.

Conclusion

Blockage of IL-33/ST2 axis reduces APAP-mediated organ injury by dampening liver chemokine release and activation of resident and infiltrating liver non-parenchymal cells.

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References

  1. Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis 2009; 29:337–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bjornsson ES. Epidemiology and risk factors for idiosyncratic drug-induced liver injury. Semin Liver Dis 2014; 34:115–22.

    Article  CAS  PubMed  Google Scholar 

  3. Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010;376:190–201.

    Article  PubMed  Google Scholar 

  4. Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525–34.

    Article  CAS  PubMed  Google Scholar 

  5. Jaeschke H, Bajt ML. Intracellular signaling mechanisms of acetaminophen-induced liver cell death. Toxicol Sci. 2006;89:31–41.

    Article  CAS  PubMed  Google Scholar 

  6. Ni HM, Jaeschke H, Ding WX. Targeting autophagy for drug-induced hepatotoxicity. Autophagy 2012;8:709–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rock KL, Latz E, Ontiveros F, Kono H. The sterile inflammatory response. Annu Rev Immunol 2010;28:321–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Marques PE, Oliveira AG, Pereira RV, David BA, Gomides LF, Saraiva AM, et al. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology. 2015;61:348–60.

    Article  CAS  PubMed  Google Scholar 

  9. Martin-Murphy BV, Holt MP, Ju C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett 2010;192:387–94.

    Article  CAS  PubMed  Google Scholar 

  10. Baekkevold ES, Roussigne M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am J Pathol. 2003;163:69–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–90.

    Article  CAS  PubMed  Google Scholar 

  12. Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA 2007;104:282–7.

    Article  CAS  PubMed  Google Scholar 

  13. Lefrancais E, Cayrol C. Mechanisms of IL-33 processing and secretion: differences and similarities between IL-1 family members. Eur Cytokine Netw. 2012;23:120–7.

    CAS  PubMed  Google Scholar 

  14. Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, et al. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J Immunol. 2012;188:3488–95.

    Article  CAS  PubMed  Google Scholar 

  15. Lefrancais E, Roga S, Gautier V, Gonzalez-de-Peredo A, Monsarrat B, Girard JP, et al. IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci USA. 2012;109:1673–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Miller AM. Role of IL-33 in inflammation and disease. J Inflamm. 2011;8:22.

    Article  CAS  Google Scholar 

  17. Hueber AJ, Alves-Filho JC, Asquith DL, Michels C, Millar NL, Reilly JH, et al. IL-33 induces skin inflammation with mast cell and neutrophil activation. Eur J Immunol. 2011;41:2229–37.

    Article  CAS  PubMed  Google Scholar 

  18. Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol. 2007;179:2551–5.

    Article  CAS  PubMed  Google Scholar 

  19. Marques PE, Oliveira AG, Pereira RV, David BA, Gomides LF, Saraiva AM, et al. Hepatic DNA deposition drives drug-induced liver injury and inflammation in mice. Hepatology. 2015;61(1):348–60.

    Article  CAS  PubMed  Google Scholar 

  20. Amaral SS, Oliveira AG, Marques PE, Quintao JL, Pires DA, Resende RR, et al. Altered responsiveness to extracellular ATP enhances acetaminophen hepatotoxicity. CCS. 2013;11:10.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Marques PE, Amaral SS, Pires DA, Nogueira LL, Soriani FM, Lima BH, et al. Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology. 2012;56:1971–82.

    Article  CAS  PubMed  Google Scholar 

  22. Pires DA, Marques PE, Pereira RV, David BA, Gomides LF, Dias AC, et al. Interleukin-4 deficiency protects mice from acetaminophen-induced liver injury and inflammation by prevention of glutathione depletion. Inflamm Res. 2014;63:61–9.

    Article  CAS  PubMed  Google Scholar 

  23. David BA, Rubino S, Moreira TG, Freitas-Lopes MA, Araujo AM, Paul NE, et al. Isolation and high-dimensional phenotyping of gastrointestinal immune cells. Immunology. 2017;151:56–70.

    Article  CAS  PubMed  Google Scholar 

  24. Marques PE, Antunes MM, David BA, Pereira RV, Teixeira MM, Menezes GB. Imaging liver biology in vivo using conventional confocal microscopy. Nat Protoc 2015;10:258–68.

    Article  CAS  PubMed  Google Scholar 

  25. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, et al. Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science. 2010;330:362–6.

    Article  CAS  PubMed  Google Scholar 

  26. Cruz LN, Guerra MT, Kruglov E, Mennone A, Garcia CR, Chen J, et al. Regulation of multidrug resistance-associated protein 2 by calcium signaling in mouse liver. Hepatology 2010;52:327–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Martin NT, Martin MU. Interleukin 33 is a guardian of barriers and a local alarmin. Nat Immunol. 2016;17:122–31.

    Article  CAS  PubMed  Google Scholar 

  28. Marvie P, Lisbonne M, L’Helgoualc’h A, Rauch M, Turlin B, Preisser L, et al. Interleukin-33 overexpression is associated with liver fibrosis in mice and humans. J Cell Mol Med. 2010;14:1726–39.

    Article  CAS  PubMed  Google Scholar 

  29. Sakai N, Van Sweringen HL, Quillin RC, Schuster R, Blanchard J, Burns JM, et al. Interleukin-33 is hepatoprotective during liver ischemia/reperfusion in mice. Hepatology. 2012;56:1468–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Arshad MI, Piquet-Pellorce C, L’Helgoualc’h A, Rauch M, Patrat-Delon S, Ezan F, et al. TRAIL but not FasL and TNFalpha, regulates IL-33 expression in murine hepatocytes during acute hepatitis. Hepatology. 2012;56:2353–62.

    Article  CAS  PubMed  Google Scholar 

  31. Arshad MI, Piquet-Pellorce C, Samson M. IL-33 and HMGB1 alarmins: sensors of cellular death and their involvement in liver pathology. Liver Int. 2012;32:1200–10.

    Article  CAS  PubMed  Google Scholar 

  32. Alves-Filho JC, Sonego F, Souto FO, Freitas A, Verri WA Jr, Auxiliadora-Martins M, et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med 2010;16:708–12.

    Article  CAS  PubMed  Google Scholar 

  33. Verri WA Jr, Souto FO, Vieira SM, Almeida SC, Fukada SY, Xu D, et al. IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann Rheum Dis 2010;69:1697–703.

    Article  CAS  PubMed  Google Scholar 

  34. David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA, Diniz AB, et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology. 2016;151:1176–91.

    Article  CAS  PubMed  Google Scholar 

  35. Hinson JA, Roberts DW, James LP. Mechanisms of acetaminophen-induced liver necrosis. Handb Exp Pharmacol 2010:369–405.

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Acknowledgements

Authors would like to thank CNPq, CAPES and FAPEMIG for financial support.

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Authors and Affiliations

  1. Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Maísa Mota Antunes, Alan Moreira Araújo, Ariane Barros Diniz, Rafaela Vaz Sousa Pereira, Débora Moreira Alvarenga, Bruna Araújo David, Maria Alice Freitas Lopes, Sarah Cozzer Marchesi, Brenda Naemi Nakagaki, Érika Carvalho, Denise Carmona Cara & Gustavo Batista Menezes

  2. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Renata Monti Rocha & Pedro Elias Marques

  3. Experimental and Molecular Immunology and Neurogenetics CNRS, University of Orleans, Orleans, France

    Bernhard Ryffel & Valérie Quesniaux

  4. Centre INRA Val de Loire, ISP UMR1282, Nouzilly, France

    Rodrigo Guabiraba Brito

  5. Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, São Paulo, Brazil

    José Carlos Alves Filho

  6. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Rafael Machado Rezende

Authors
  1. Maísa Mota Antunes
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  2. Alan Moreira Araújo
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  3. Ariane Barros Diniz
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  4. Rafaela Vaz Sousa Pereira
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  5. Débora Moreira Alvarenga
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  6. Bruna Araújo David
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  8. Maria Alice Freitas Lopes
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  9. Sarah Cozzer Marchesi
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  10. Brenda Naemi Nakagaki
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  11. Érika Carvalho
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  12. Pedro Elias Marques
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  13. Bernhard Ryffel
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  14. Valérie Quesniaux
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  15. Rodrigo Guabiraba Brito
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  16. José Carlos Alves Filho
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  17. Denise Carmona Cara
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  18. Rafael Machado Rezende
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  19. Gustavo Batista Menezes
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Corresponding author

Correspondence to Gustavo Batista Menezes.

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Responsible Editor: Mauro Teixeira.

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Antunes, M.M., Araújo, A.M., Diniz, A.B. et al. IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation. Inflamm. Res. 67, 77–88 (2018). https://doi.org/10.1007/s00011-017-1098-3

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  • DOI: https://doi.org/10.1007/s00011-017-1098-3

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