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Inhibition of FcεRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes

Nature Medicine volume 13, pages 1375–1381 (2007)Cite this article

Abstract

Atopic allergy is characterized by an increase in IgE antibodies that signal through the high-affinity Fcε receptor (FcεRI) to induce the release of inflammatory mediators from mast cells. For unknown reasons, the prevalence of allergic diseases has recently increased steeply in the developed world1. However, this increase has not been mirrored in developing countries2, even though IgE concentrations are often greatly elevated in individuals from these countries, owing to nonspecific IgE induction by universally present parasitic worms3. Here we offer one explanation for this paradox based on the properties of ES-62, a molecule secreted by filarial nematodes4. We found that highly purified, endotoxin-free ES-62 directly inhibits the FcεRI-induced release of allergy mediators from human mast cells by selectively blocking key signal transduction events, including phospholipase D–coupled, sphingosine kinase–mediated calcium mobilization and nuclear factor-κB activation. ES-62 mediates these effects by forming a complex with Toll-like receptor 4, which results in the sequestration of protein kinase C-α (PKC-α). This causes caveolae/lipid raft–mediated, proteasome-independent degradation of PKC-α, a molecule important for the coupling of FcεRI to phospholipase D and mast cell activation. We also show that ES-62 is able to protect mice from mast cell–dependent hypersensitivity in the skin and lungs, indicating that it has potential as a novel therapeutic for allergy.

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Figure 1: ES-62 inhibition of FcεRI-mediated Ca2+ mobilization and degranulation of human BMMC correlates with downregulation of PKC-α expression.
Figure 2: ES-62–mediated inhibition of proinflammatory mediator production from BMMCs correlates with decreased NF-κB activity, and TLR4 antisense oligonucleotides prevent ES-62 modulation of mast cell function.
Figure 3: ES-62 forms a complex with TLR4 and PKC-α and is internalized into vesicular compartments.
Figure 4: In vivo exposure to ES-62 inhibits mouse mast-cell activity ex vivo and protects against immediate hypersensitivity.

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References

  1. Burney, P.G.J. Epidemiological trends. in Asthma (eds. Barnes, P.J., Grunstein, M.M., Leff, A.R. & Woolcock, A.J.) 35–47 (Lippincott Raven, Philadelphia, 1997).

    Google Scholar 

  2. McKay, D.M. The beneficial helminth parasite? Parasitology 132, 1–12 (2006).

    Article  CAS  Google Scholar 

  3. Wilson, M.S. & Maizels, R.M. Regulation of allergy and autoimmunity in helminth infection. Clin. Rev. Allergy Immunol. 26, 35–50 (2004).

    Article  CAS  Google Scholar 

  4. Harnett, W., McInnes, I.B. & Harnett, M.M. ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential. Immunol. Lett. 94, 27–33 (2004).

    Article  CAS  Google Scholar 

  5. Kinet, J.P. The high-affinity IgE receptor (FcεRI): from physiology to pathology. Annu. Rev. Immunol. 17, 931–972 (1999).

    Article  CAS  Google Scholar 

  6. Lal, R.B., Paranjape, R.S., Briles, D.E., Nutman, T.B. & Ottesen, E.A. Circulating parasite antigen(s) in lymphatic filariasis—use of monoclonal-antibodies to phosphocholine for immunodiagnosis. J. Immunol. 138, 3454–3460 (1987).

    CAS  PubMed  Google Scholar 

  7. Melendez, A.J. & Khaw, A.K. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255–17262 (2002).

    Article  CAS  Google Scholar 

  8. Melendez, A.J., Harnett, M.M. & Allen, J.M. Crosstalk between ARF6 and protein kinase Calpha in FcγRI-mediated activation of phospholipase D1. Curr. Biol. 11, 869–874 (2001).

    Article  CAS  Google Scholar 

  9. Li, G., Lucas, J.J. & Gelfand, E.W. Protein kinase Cα, βI and βII isozymes regulate cytokine production in mast cells through MEKK2/ERK5-dependent and independent pathways. Cell. Immunol. 238, 10–18 (2005).

    Article  CAS  Google Scholar 

  10. Abdel-Raheem, I.T. et al. Protein kinase C-α mediates TNF release process in RBL-2H3 mast cells. Br. J. Pharmacol. 145, 415–423 (2005).

    Article  CAS  Google Scholar 

  11. Coward, W.R. et al. NF-κB and TNF-α: a positive autocrine loop in human lung mast cells? J. Immunol. 169, 5287–5293 (2002).

    Article  Google Scholar 

  12. Stassen, M. et al. IL-9 and IL-13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF-κB is decisively involved in the expression of IL-9. J. Immunol. 166, 4391–4398 (2001).

    Article  CAS  Google Scholar 

  13. Jeong, H.J. et al. Role of Ca2+ on TNF-α and IL-6 secretion from RBL-2H3 mast cells. Cell. Signal. 14, 633–639 (2002).

    Article  CAS  Google Scholar 

  14. Marquardt, D.L. & Walker, L.L. Dependence of mast cell IgE-mediated cytokine production on nuclear factor-κB activity. J. Allergy Clin. Immunol. 105, 500–505 (2000).

    Article  CAS  Google Scholar 

  15. Dolmetsch, R.E., Xu, K. & Lewis, R.S. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392, 933–936 (1998).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  17. Rhee, S.H. & Hwang, D. Murine Toll-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF κB and expression of the inducible cyclooxygenase. J. Biol. Chem. 275, 34035–34040 (2000).

    Article  CAS  Google Scholar 

  18. Powner, D.J., Hodgkin, M.N. & Wakelam, M.J. Antigen-stimulated activation of phospholipase D1b by Rac1, ARF6, and PKCα in RBL-2H3 cells. Mol. Biol. Cell 13, 1252–1262 (2002).

    Article  CAS  Google Scholar 

  19. Leontieva, O.V. & Black, J.D. Identification of two distinct pathways of protein kinase Cα down-regulation in intestinal epithelial cells. J. Biol. Chem. 279, 5788–5801 (2004).

    Article  CAS  Google Scholar 

  20. Li, L., Cousart, S., Hu, J. & McCall, C.E. Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J. Biol. Chem. 275, 23340–23345 (2000).

    Article  CAS  Google Scholar 

  21. Smith, L. et al. Activation of atypical protein kinase Cζ by caspase processing and degradation by the ubiquitin-proteasome system. J. Biol. Chem. 275, 40620–40627 (2000).

    Article  CAS  Google Scholar 

  22. Bryce, P.J. et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20, 381–392 (2004).

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Nigo, Y.I. et al. Regulation of allergic airway inflammation through Toll-like receptor 4–mediated modification of mast cell function. Proc. Natl. Acad. Sci. USA 103, 2286–2291 (2006).

    Article  CAS  Google Scholar 

  25. Bradding, P., Walls, A.F. & Holgate, S.T. The role of the mast cell in the pathophysiology of asthma. J. Allergy Clin. Immunol. 117, 1277–1284 (2006).

    Article  CAS  Google Scholar 

  26. Hamelmann, E. et al. Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography. Am. J. Respir. Crit. Care Med. 156, 766–775 (1997).

    Article  CAS  Google Scholar 

  27. Harnett, W., Harnett, M.M. & Byron, O. Structural/functional aspects of ES-62—a secreted immunomodulatory phosphorylcholine-containing filarial nematode glycoprotein. Curr. Protein Pept. Sci. 4, 59–71 (2003).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Goodridge, H.S., Stepek, G., Harnett, W. & Harnett, M.M. Signalling mechanisms underlying subversion of the immune response by the filarial nematode secreted product ES-62. Immunology 115, 296–304 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the YonH Loo Lin School of Medicine, the National University of Singapore (A.J.M.) and the Wellcome Trust (W.H. and M.M.H.).

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Authors and Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD9, 117597, Singapore

    Alirio J Melendez, Peter N Pushparaj & Hwee Kee Tay

  2. Division of Immunology, Infection and Inflammation, Glasgow University, 120 University Place, Glasgow, G12 8TA, UK

    Margaret M Harnett & Charles P McSharry

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive MD2, 117597, Singapore

    WS Fred Wong

  4. Strathclyde Institute of Pharmacy and Biomedical Sciences, Strathclyde University, 27 Taylor Street, Glasgow, G4 0NR, UK

    William Harnett

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  1. Alirio J Melendez
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Correspondence to William Harnett.

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Melendez, A., Harnett, M., Pushparaj, P. et al. Inhibition of FcεRI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 13, 1375–1381 (2007). https://doi.org/10.1038/nm1654

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