Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells.
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.
Idzko
Marco
M
Department of Pulmonary Medicine, Erasmus University Medical Center, Dr. Molewaterplein 50, P.O. Box 1738, 3000 DR Rotterdan, The Netherlands. marco.idzko@uniklinik-freiburg.de
Hammad
Hamida
H
van Nimwegen
Menno
M
Kool
Mirjam
M
Willart
Monique A M
MA
Muskens
Femke
F
Hoogsteden
Henk C
HC
Luttmann
Werner
W
Ferrari
Davide
D
Di Virgilio
Francesco
F
Virchow
J Christian
JC
Lambrecht
Bart N
BN
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D013498:Suramin; D000255:Adenosine Triphosphate