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

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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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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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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The authors declare no competing financial interests.

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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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