Rationale: P2X7R-deficiency has been shown to be associated with a less severe outcome in acute and chronic inflammatory disorders. Recently, we demonstrated that extracellular adenosine triphosphate (ATP) is involved in the pathogenesis of asthma by modulating the function of dendritc cells (DCs). However, the role of the purinergic receptor subtype P2X7 is unknown. Objectives: To elucidate the role of P2X7R in allergic airway inflammation (AAI) in vitro and in vivo. Methods: P2X7R-Expression was measured in lung tissue and immune cells of mice and/or human being with allergic asthma. By using a specific P2X7R-antagonist and P2X7R-deficient animals the role of this receptor in acute and chronic experimental asthma was explored. Measurements and Main Results: P2X7R was found to be up-regulated during acute and chronic asthmatic airway inflammation in mice and humans. In vivo experiments revealed the functional relevance of this finding, as selective P2X7R-inhibition or - deficiency was associated with reduced features of acute and chronic asthma in the OVA- alum and/or HDM- model of AAI. Experiments with bone marrow-chimeras emphasized that P2X7R expression on haematopoietic cells is responsible for the pro-asthmatic effects of P2X7R signalling. In the DC driven model of allergic airway inflammation, P2X7R-deficient DCs showed a reduced capacity to induce Th2 immunity in vivo. Finally up-regulation of P2X7R on BAL-macrophages and blood eosinophils could be observed in patients with chronic asthma. Conclusions: In summary, our data suggest that targeting P2X7R on haematopoietic cells (e.g. DCs or eosinophils) might be new therapeutic option for the treatment of asthma.
A potential role for P2X7R in allergic airway inflammation in mice and humans
FERRARI, Davide;DI VIRGILIO, Francesco;
2011
Abstract
Rationale: P2X7R-deficiency has been shown to be associated with a less severe outcome in acute and chronic inflammatory disorders. Recently, we demonstrated that extracellular adenosine triphosphate (ATP) is involved in the pathogenesis of asthma by modulating the function of dendritc cells (DCs). However, the role of the purinergic receptor subtype P2X7 is unknown. Objectives: To elucidate the role of P2X7R in allergic airway inflammation (AAI) in vitro and in vivo. Methods: P2X7R-Expression was measured in lung tissue and immune cells of mice and/or human being with allergic asthma. By using a specific P2X7R-antagonist and P2X7R-deficient animals the role of this receptor in acute and chronic experimental asthma was explored. Measurements and Main Results: P2X7R was found to be up-regulated during acute and chronic asthmatic airway inflammation in mice and humans. In vivo experiments revealed the functional relevance of this finding, as selective P2X7R-inhibition or - deficiency was associated with reduced features of acute and chronic asthma in the OVA- alum and/or HDM- model of AAI. Experiments with bone marrow-chimeras emphasized that P2X7R expression on haematopoietic cells is responsible for the pro-asthmatic effects of P2X7R signalling. In the DC driven model of allergic airway inflammation, P2X7R-deficient DCs showed a reduced capacity to induce Th2 immunity in vivo. Finally up-regulation of P2X7R on BAL-macrophages and blood eosinophils could be observed in patients with chronic asthma. Conclusions: In summary, our data suggest that targeting P2X7R on haematopoietic cells (e.g. DCs or eosinophils) might be new therapeutic option for the treatment of asthma.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
