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Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells

Nature Medicine volume 13, pages 913–919 (2007)Cite this article

Abstract

Extracellular ATP serves as a danger signal to alert the immune system of tissue damage by acting on P2X or P2Y receptors. Here we show that allergen challenge causes acute accumulation of ATP in the airways of asthmatic subjects and mice with experimentally induced asthma. All the cardinal features of asthma, including eosinophilic airway inflammation, Th2 cytokine production and bronchial hyper-reactivity, were abrogated when lung ATP levels were locally neutralized using apyrase or when mice were treated with broad-spectrum P2-receptor antagonists. In addition to these effects of ATP in established inflammation, Th2 sensitization to inhaled antigen was enhanced by endogenous or exogenous ATP. The adjuvant effects of ATP were due to the recruitment and activation of lung myeloid dendritic cells that induced Th2 responses in the mediastinal nodes. Together these data show that purinergic signaling has a key role in allergen-driven lung inflammation that is likely to be amenable to therapeutic intervention.

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Figure 1: Release of ATP during asthmatic airway inflammation in humans and mice.
Figure 2: Neutralizing airway ATP levels inhibits eosinophilic airway inflammation.
Figure 3: Intrapulmonary application of the P2R antagonist suramin inhibits cardinal features of asthma.
Figure 4: The effect of ATPγS on the induction of Th2 immunity and DC migration in vivo.
Figure 5: Effect of ATP on the capacity of DCs to prime for Th2 responses in vivo.
Figure 6: The P2R antagonist suramin inhibits the induction of airway Th2 responses by endogenous lung mDCs.

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References

  1. Wills-Karp, M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 17, 255–281 (1999).

    Article  CAS  Google Scholar 

  2. Adriaensen, D. & Timmermans, J.P. Purinergic signalling in the lung: important in asthma and COPD? Curr. Opin. Pharmacol. 4, 207–214 (2004).

    Article  CAS  Google Scholar 

  3. Spicuzza, L., Di Maria, G. & Polosa, R. Adenosine in the airways: implications and applications. Eur. J. Pharmacol. 533, 77–88 (2006).

    Article  CAS  Google Scholar 

  4. Mohsenin, A. & Blackburn, M.R. Adenosine signaling in asthma and chronic obstructive pulmonary disease. Curr. Opin. Pulm. Med. 12, 54–59 (2006).

    Article  CAS  Google Scholar 

  5. van den Berge, M., Polosa, R., Kerstjens, H.A. & Postma, D.S. The role of endogenous and exogenous AMP in asthma and chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 114, 737–746 (2004).

    Article  CAS  Google Scholar 

  6. Burnstock, G. Pathophysiology and therapeutic potential of purinergic signaling. Pharmacol. Rev. 58, 58–86 (2006).

    Article  CAS  Google Scholar 

  7. Khakh, B.S. & North, R.A. P2X receptors as cell-surface ATP sensors in health and disease. Nature 442, 527–532 (2006).

    Article  CAS  Google Scholar 

  8. Bours, M.J., Swennen, E.L., Di Virgilio, F., Cronstein, B.N. & Dagnelie, P.C. Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol. Ther. 112, 358–404 (2006).

    Article  CAS  Google Scholar 

  9. Ferrari, D. et al. Extracellular ATP triggers IL-1 beta release by activating the purinergic P2Z receptor of human macrophages. J. Immunol. 159, 1451–1458 (1997).

    CAS  PubMed  Google Scholar 

  10. Pelleg, A. & Schulman, E.S. Adenosine 5′-triphosphate axis in obstructive airway diseases. Am. J. Ther. 9, 454–464 (2002).

    Article  Google Scholar 

  11. Idzko, M. et al. Nucleotides induce chemotaxis and actin polymerization in immature but not mature human dendritic cells via activation of pertussis toxin-sensitive P2y receptors. Blood 100, 925–932 (2002).

    Article  CAS  Google Scholar 

  12. la Sala, A. et al. Extracellular ATP induces a distorted maturation of dendritic cells and inhibits their capacity to initiate Th1 responses. J. Immunol. 166, 1611–1617 (2001).

    Article  CAS  Google Scholar 

  13. la Sala, A. et al. Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes. Blood 99, 1715–1722 (2002).

    Article  CAS  Google Scholar 

  14. Wilkin, F., Stordeur, P., Goldman, M., Boeynaems, J.M. & Robaye, B. Extracellular adenine nucleotides modulate cytokine production by human monocyte-derived dendritic cells: dual effect on IL-12 and stimulation of IL-10. Eur. J. Immunol. 32, 2409–2417 (2002).

    Article  CAS  Google Scholar 

  15. Ferrari, D. et al. The P2X7 receptor: a key player in IL-1 processing and release. J. Immunol. 176, 3877–3883 (2006).

    Article  CAS  Google Scholar 

  16. Idzko, M. et al. Stimulation of P2 purinergic receptors induces the release of eosinophil cationic protein and interleukin-8 from human eosinophils. Br. J. Pharmacol. 138, 1244–1250 (2003).

    Article  CAS  Google Scholar 

  17. Coade, S.B. & Pearson, J.D. Metabolism of adenine nucleotides in human blood. Circ. Res. 65, 531–537 (1989).

    Article  CAS  Google Scholar 

  18. Di Virgilio, F. et al. Nucleotide receptors: an emerging family of regulatory molecules in blood cells. Blood 97, 587–600 (2001).

    Article  CAS  Google Scholar 

  19. Schnurr, M. et al. Extracellular ATP and TNF-alpha synergize in the activation and maturation of human dendritic cells. J. Immunol. 165, 4704–4709 (2000).

    Article  CAS  Google Scholar 

  20. de Heer, H.J. et al. Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J. Exp. Med. 200, 89–98 (2004).

    Article  CAS  Google Scholar 

  21. Lambrecht, B.N. et al. Myeloid dendritic cells induce Th2 responses to inhaled antigen, leading to eosinophilic airway inflammation. J. Clin. Invest. 106, 551–559 (2000).

    Article  CAS  Google Scholar 

  22. Lambrecht, B.N. & Hammad, H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat. Rev. Immunol. 3, 994–1003 (2003).

    Article  CAS  Google Scholar 

  23. van Rijt, L.S. et al. In vivo depletion of lung CD11c+ dendritic cells during allergen challenge abrogates the characteristic features of asthma. J. Exp. Med. 201, 981–991 (2005).

    Article  CAS  Google Scholar 

  24. Idzko, M. et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J. Clin. Invest. 116, 2935–2944 (2006).

    Article  CAS  Google Scholar 

  25. Abbracchio, M.P. et al. International Union of Pharmacology LVIII: Update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol. Rev. 58, 281–341 (2006).

    Article  CAS  Google Scholar 

  26. Vermaelen, K.Y., Carro-Muino, I., Lambrecht, B.N. & Pauwels, R.A. Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes. J. Exp. Med. 193, 51–60 (2001).

    Article  CAS  Google Scholar 

  27. la Sala, A. et al. Alerting and tuning the immune response by extracellular nucleotides. J. Leukoc. Biol. 73, 339–343 (2003).

    Article  CAS  Google Scholar 

  28. Beigi, R., Kobatake, E., Aizawa, M. & Dubyak, G.R. Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase. Am. J. Physiol. 276, C267–C278 (1999).

    Article  CAS  Google Scholar 

  29. Pitchford, S.C. & Page, C.P. Platelet activation in asthma: integral to the inflammatory response. Clin. Exp. Allergy 36, 399–401 (2006).

    Article  CAS  Google Scholar 

  30. Kowal, K., Pampuch, A., Kowal-Bielecka, O., DuBuske, L.M. & Bodzenta-Lukaszyk, A. Platelet activation in allergic asthma patients during allergen challenge with Dermatophagoides pteronyssinus. Clin. Exp. Allergy 36, 426–432 (2006).

    Article  CAS  Google Scholar 

  31. Robson, S.C. et al. Loss of ATP diphosphohydrolase activity with endothelial cell activation. J. Exp. Med. 185, 153–163 (1997).

    Article  CAS  Google Scholar 

  32. Chen, Y. et al. ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 314, 1792–1795 (2006).

    Article  CAS  Google Scholar 

  33. Huh, J.C. et al. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J. Exp. Med. 198, 19–30 (2003).

    Article  CAS  Google Scholar 

  34. Kohl, J. et al. A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma. J. Clin. Invest. 116, 783–796 (2006).

    Article  CAS  Google Scholar 

  35. Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).

    Article  CAS  Google Scholar 

  36. Harris, N.L., Watt, V., Ronchese, F. & Le Gros, G. Differential T cell function and fate in lymph node and nonlymphoid tissues. J. Exp. Med. 195, 317–326 (2002).

    Article  CAS  Google Scholar 

  37. Ferrari, D. et al. Activation of human eosinophils via P2 receptors: novel findings and future perspectives. J. Leukoc. Biol. 79, 7–15 (2006).

    Article  CAS  Google Scholar 

  38. Piggott, D.A. et al. MyD88-dependent induction of allergic Th2 responses to intranasal antigen. J. Clin. Invest. 115, 459–467 (2005).

    Article  CAS  Google Scholar 

  39. Granstein, R.D. et al. Augmentation of cutaneous immune responses by ATP gamma S: purinergic agonists define a novel class of immunologic adjuvants. J. Immunol. 174, 7725–7731 (2005).

    Article  CAS  Google Scholar 

  40. Gallucci, S. & Matzinger, P. Danger signals: SOS to the immune system. Curr. Opin. Immunol. 13, 114–119 (2001).

    Article  CAS  Google Scholar 

  41. Di Virgilio, F. Purinergic mechanism in the immune system: a signal of danger for dendritic cells. Purinergic Signal. 1, 205–209 (2005).

    Article  CAS  Google Scholar 

  42. Mizumoto, N. et al. CD39 is the dominant Langerhans cell–associated ecto-NTPDase: modulatory roles in inflammation and immune responsiveness. Nat. Med. 8, 358–365 (2002).

    Article  CAS  Google Scholar 

  43. Hollander, G.A., Zuklys, S., Forster, E. & Krenger, W. On costimulatory signals and T cell tolerance: relevance for transplantation immunity. Transplant. Proc. 31, 25S–31S (1999).

    Article  CAS  Google Scholar 

  44. Laubinger, W., Tulapurkar, M.E., Schafer, R. & Reiser, G. Distinct mono- and dinucleotide-specific P2Y receptors in A549 lung epithelial cells: different control of arachidonic acid release and nitric oxide synthase expression. Eur. J. Pharmacol. 543, 1–7 (2006).

    Article  CAS  Google Scholar 

  45. Muller, T. et al. The P2Y14 receptor of airway epithelial cells: coupling to intracellular Ca2+ and IL-8 secretion. Am. J. Respir. Cell Mol. Biol. 33, 601–609 (2005).

    Article  Google Scholar 

  46. Douillet, C.D., Robinson, W.P., III, Milano, P.M., Boucher, R.C. & Rich, P.B. Nucleotides induce IL-6 release from human airway epithelia via P2Y2 and p38 MAPK-dependent pathways. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L734–L746 (2006).

    Article  CAS  Google Scholar 

  47. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440, 228–232 (2006).

    Article  CAS  Google Scholar 

  48. Ogura, Y., Sutterwala, F.S. & Flavell, R.A. The inflammasome: first line of the immune response to cell stress. Cell 126, 659–662 (2006).

    Article  CAS  Google Scholar 

  49. Lommatzsch, M. et al. The course of allergen-induced leukocyte infiltration in human and experimental asthma. J. Allergy Clin. Immunol. 118, 91–97 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by an Emmy Noether Fellowship to M.I. from the Deutsche Forschungsgemeinshaft (DFG ID7/3-1) and by a Netherlands Organization for Scientific Research Vidi grant to B.N.L. and Veni grant to H.H. B.N.L. is supported by a European Respiratory Society Romain Pauwels research grant.

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Erasmus University Medical Center, Dr. Molewaterplein 50, P.O. Box 1738, Rotterdan, 3000 DR, The Netherlands

    Marco Idzko, Hamida Hammad, Menno van Nimwegen, Mirjam Kool, Monique A M Willart, Femke Muskens, Henk C Hoogsteden & Bart N Lambrecht

  2. Department of Pulmonary Medicine, University Hospital Freiburg, Killianstrasse 5, Freiburg, 79106, Germany

    Marco Idzko

  3. Department of Pulmonary Medicine, University Hospital Rostock, Ernst-Heydemann-Strasse 6, Postfach 10 08 88, Rostock, 18055, Germany

    Werner Luttmann & J Christian Virchow Jr

  4. Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Via Borsari 46, Ferrara, I-44100, Italy

    Davide Ferrari & Francesco Di Virgilio

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Contributions

M.I., H.H., D.F., F.D.V., H.C.H. and B.N.L. designed and performed experiments, interpreted and analyzed data, generated figures and wrote the manuscript. M.v.N., M.K., F.M. and M.A.M.W. performed in vitro and in vivo mouse experiments. W.L. and J.C.V. performed and analyzed the human experiments.

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Correspondence to Marco Idzko or Bart N Lambrecht.

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Idzko, M., Hammad, H., van Nimwegen, M. et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med 13, 913–919 (2007). https://doi.org/10.1038/nm1617

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