The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88

  • A Retraction to this article was published on 19 July 2011

Abstract

Sepsis is one of the most challenging health problems worldwide. Here we found that phagocytes from patients with sepsis had considerable upregulation of Toll-like receptor 4 (TLR4) and TLR2; however, shock-inducing inflammatory responses mediated by these TLRs were inhibited by ES-62, an immunomodulator secreted by the filarial nematode Acanthocheilonema viteae. ES-62 subverted TLR4 signaling to block TLR2- and TLR4-driven inflammatory responses via autophagosome-mediated downregulation of the TLR adaptor-transducer MyD88. In vivo, ES-62 protected mice against endotoxic and polymicrobial septic shock by TLR4-mediated induction of autophagy and was protective even when administered after the induction of sepsis. Given that the treatments for septic shock at present are inadequate, the autophagy-dependent mechanism of action by ES-62 might form the basis for urgently needed therapeutic intervention against this life-threatening condition.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Effects of ES-62 on human macrophages.
Figure 2: Effect of ES-62 on phagocytes from patients with sepsis.
Figure 3: ES-62 targets TLR4 and MyD88 to early and late endosomes.
Figure 4: ES-62 induces autophagosome formation.
Figure 5: ES-62 protects against endotoxic shock.
Figure 6: ES-62 protects against polymicrobial sepsis.
Figure 7: ES-62 protects via autophagy in vivo.
Figure 8: Therapeutic role for ES-62 in polymicrobial sepsis.

Change history

  • 24 June 2011

    The authors wish to note the following. Irregularities have been identified in some of the figures in this paper. The conclusions drawn from these data, that ES-62 protects against the development of pathology in the sepsis models and results in the induction of autophagy in macrophages, cannot be made. As these conclusions constitute major components of the paper, we wish to retract this paper.

References

  1. 1

    Dombrovskiy, V.Y., Martin, A.A., Sunderram, J. & Paz, H.L. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit. Care Med. 35, 1244–1250 (2007).

    Article  Google Scholar 

  2. 2

    Padkin, A. et al. Epidemiology of severe sepsis occurring in the first 24 h in intensive care units in England, Wales, and Northern Ireland. Crit. Care Med. 31, 2332–2338 (2003).

    Article  Google Scholar 

  3. 3

    Vincent, J.L. et al. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. J. Am. Med. Assoc. 274, 639–644 (1995).

    CAS  Article  Google Scholar 

  4. 4

    Martin, G.S., Mannino, D.M., Eaton, S. & Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003).

    Article  Google Scholar 

  5. 5

    Balk, R.A. Severe sepsis and septic shock. Definitions, epidemiology, and clinical manifestations. Crit. Care Clin. 16, 179–192 (2000).

    CAS  Article  Google Scholar 

  6. 6

    Alexander, C. & Rietschel, E.T. Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res. 7, 167–202 (2001).

    CAS  PubMed  Google Scholar 

  7. 7

    Janeway, C.A. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Gay, N.J. & Gangloff, M. Structure and function of Toll receptors and their ligands. Annu. Rev. Biochem. 76, 141–165 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Doyle, S.L. & O'Neill, L.A. Toll-like receptors: from the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochem. Pharmacol. 72, 1102–1113 (2006).

    CAS  Article  Google Scholar 

  10. 10

    O'Neill, L.A. & Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol. 7, 353–364 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Parrillo, J.E. et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann. Intern. Med. 113, 227–242 (1990).

    CAS  Article  Google Scholar 

  12. 12

    Exley, A.R., Leese, T., Holliday, M.P., Swann, R.A. & Cohen, J. Endotoxaemia and serum tumour necrosis factor as prognostic markers in severe acute pancreatitis. Gut 33, 1126–1128 (1992).

    CAS  Article  Google Scholar 

  13. 13

    Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Bustin, M. At the crossroads of necrosis and apoptosis, signaling to multiple cellular targets by HMGB1. Sci. STKE 151, PE39 (2002).

    Google Scholar 

  15. 15

    Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Goodridge, H.S. et al. Immunomodulation via novel use of TLR4 by the filarial nematode phosphorylcholine-containing secreted product, ES-62. J. Immunol. 174, 284–293 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Melendez, A.J. et al. Inhibition of FcɛRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat. Med. 13, 1375–1381 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Salomão, R. et al. TLR signaling pathway in patients with sepsis. Shock 1, 73–77 (2008).

    Article  Google Scholar 

  19. 19

    Weighardt, H. & Holzmann, B. Role of Toll-like receptor responses for sepsis pathogenesis. Immunobiology 212, 715–722 (2008).

    Article  Google Scholar 

  20. 20

    Delgado, M.A. & Deretic, V. Toll-like receptors in control of immunological autophagy. Cell Death Differ. 16, 976–983 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Deretic, V. Multiple regulatory effector roles of autophagy in immunity. Curr. Opin. Immunol. 21, 53–62 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Klionsky, D.J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151–175 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Mizushima, N. et al. Methods in mammalian autophagy research. Cell 1403, 313–326 (2010).

    Article  Google Scholar 

  24. 24

    Phillip, D.R. & Parrillo, J.E. Mediator modulation therapy of severe sepsis and septic shock: does it work? Crit. Care Med. 32, 282–286 (2004).

    Article  Google Scholar 

  25. 25

    Eichacker, P.Q. et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am. J. Respir. Crit. Care Med. 166, 1197–1205 (2002).

    Article  Google Scholar 

  26. 26

    Hubbard, W.J. et al. Cecal ligation and puncture. Shock 1, 52–57 (2005).

    Article  Google Scholar 

  27. 27

    Li, Y., Karlin, A., Loike, J.D. & Silverstein, S.C. A critical concentration of neutrophils is required for effective bacterial killing in suspension. Proc. Natl. Acad. Sci. USA 99, 8289–8294 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Weighardt, H. et al. Cutting edge: myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection. J. Immunol. 169, 2823–2827 (2002).

    CAS  Article  Google Scholar 

  29. 29

    Puneet, P. et al. SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis. Science 328, 1290–1294 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Sethu, S., Pushparaj, P.N. & Melendez, A.J. TNFα-induced inflammatory responses in vivo are mediated by PLD1. PLoS ONE 5, e10506 (2010).

    Article  Google Scholar 

  31. 31

    Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456, 264–268 (2008).

    CAS  Article  Google Scholar 

  32. 32

    Lee, H.-M. et al. Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1. J. Immunol. 186, 1248–1258 (2011).

    CAS  Article  Google Scholar 

  33. 33

    Goodridge, H.S. et al. Modulation of macrophage cytokine production by ES-62, a secreted product of the filarial nematode Acanthocheilonema viteae. J. Immunol. 167, 940–945 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Henneke, P. et al. Cellular activation, phagocytosis, and bactericidal activity against group B streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J. Immunol. 169, 3970–3977 (2002).

    CAS  Article  Google Scholar 

  35. 35

    Horng, T., Barton, G.M. & Medzhitov, R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat. Immunol. 2, 835–841 (2001).

    CAS  Article  Google Scholar 

  36. 36

    Horng, T. et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002).

    CAS  Article  Google Scholar 

  37. 37

    Doz, E. et al. Acylation determines the toll-like receptor (TLR)-dependent positive versus TLR2-, mannose receptor-, and SIGNR1-independent negative regulation of pro-inflammatory cytokines by mycobacterial lipomannan. J. Biol. Chem. 282, 26014–26025 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Ferwerda, B. et al. Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock. Proc. Natl. Acad. Sci. USA 106, 10272–10277 (2009).

    CAS  Article  Google Scholar 

  39. 39

    Daubeuf, B. et al. TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock. J. Immunol. 179, 6107–6114 (2007).

    CAS  Article  Google Scholar 

  40. 40

    Sha, T. et al. Therapeutic effects of TAK-242, a novel selective Toll-like receptor 4 signal transduction inhibitor, in mouse endotoxin shock model. Eur. J. Pharmacol. 571, 231–239 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Leon, C.G., Tory, R., Jia, J., Sivak, O. & Wasan, K.M. Discovery and development of toll-like receptor 4 (TLR4) antagonists: a new paradigm for treating sepsis and other diseases. Pharm. Res. 25, 1751–1761 (2008).

    CAS  Article  Google Scholar 

  42. 42

    Bone, R.C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis: members of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Crit. Care Med. 20, 864–874 (1992).

    Article  Google Scholar 

  43. 43

    McInnes, I.B. et al. A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J. Immunol. 171, 2127–2133 (2003).

    CAS  Article  Google Scholar 

  44. 44

    Harnett, M.M. Laser scanning cytometry: understanding the immune system in situ. Nat. Rev. Immunol. 11, 897–904 (2007).

    Article  Google Scholar 

  45. 45

    Morton, A.M. et al. Inverse Rap1 and phospho-ERK expression discriminate the maintenance phase of tolerance and priming of antigen-specific CD4+ T cells in vitro and in vivo. J. Immunol. 179, 8026–8034 (2007).

    CAS  Article  Google Scholar 

  46. 46

    Melendez, A.J. & Ibrahim, F. Antisense knockdown of sphingosine kinase 1 in human macrophages inhibits C5a receptor-dependent signal transduction, Ca2+ signals, enzyme release, cytokine production and chemotaxis. J. Immunol. 173, 1596–1603 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Ibrahim, F.B., Pang, S.J. & Melendez, A.J. Anaphylatoxin signaling in human neutrophils: A key role for sphingosine kinase. J. Biol. Chem. 279, 44802–44811 (2004).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Supported by the Medical Research Council UK (G0700794), the Biomedical Research Council of Singapore, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council UK and the American Asthma Foundation.

Author information

Affiliations

Authors

Contributions

P.P., M.A.M., H.K.T., L.A.-R. and J.R. did experiments; S.M.M. supplied reagents; A.J.M. conceived of the study; A.J.M., M.M.H., S.P. and W.H. planned the experiments, supervised the study and wrote the paper; and all authors analyzed data.

Corresponding author

Correspondence to Alirio J Melendez.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 263 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Puneet, P., McGrath, M., Tay, H. et al. The helminth product ES-62 protects against septic shock via Toll-like receptor 4–dependent autophagosomal degradation of the adaptor MyD88. Nat Immunol 12, 344–351 (2011). https://doi.org/10.1038/ni.2004

Download citation

Further reading