A potential role for P2X7R in allergic airway inflammation in mice and humans.

Abstract

P2X₇R deficiency is associated with a less severe outcome in acute and chronic inflammatory disorders. Recently, we demonstrated that extracellular adenosine triphosphate is involved in the pathogenesis of asthma by modulating the function of dendritic cells (DCs). However, the role of the purinergic receptor subtype P2X₇ is unknown. To elucidate the role of P2X₇R in allergic airway inflammation (AAI) in vitro and in vivo, P2X₇R expression was measured in lung tissue and immune cells of mice or in humans 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. 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 because selective P2X₇R inhibition or P2X₇R deficiency was associated with reduced features of acute and chronic asthma in the ovalbumin-alum or HDM model of AAI. Experiments with bone marrow chimeras emphasized that P2X₇R expression on hematopoietic cells is responsible for the proasthmatic effects of P2X₇R signaling. In the DC-driven model of AAI, P2X₇R-deficient DCs showed a reduced capacity to induce Th2 immunity in vivo. Up-regulation of P2X₇R on BAL macrophages and blood eosinophils could be observed in patients with chronic asthma. Our data suggest that targeting P2X₇R on hematopoietic cells (e.g., DCs or eosinophils) might be a new therapeutic option for the treatment of asthma.

• Authors: Tobias Müller, Rodolfo Paula Vieira, Melanie Grimm, Thorsten Dürk, Sanja Cicko, Robert Zeiser, Thilo Jakob, Stefan F Martin, Britta Blumenthal, Stephan Sorichter, Davide Ferrari, Francesco Di Virgillio, Marco Idzko
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 44 Issue 4 Pg. 456-64 (Apr 2011) ISSN: 1535-4989 [Electronic] United States
• PMID: 20508067 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X7
• Adenosine Triphosphate

Topics

• Acute Disease
• Adenosine Triphosphate (pharmacology)
• Animals
• Asthma (complications, immunology, metabolism, pathology)
• Bone Marrow Cells (cytology)
• Bronchoalveolar Lavage Fluid (cytology)
• Case-Control Studies
• Cell Movement (drug effects)
• Chronic Disease
• Dendritic Cells (cytology, drug effects, immunology, metabolism)
• Eosinophils (drug effects, immunology)
• Extracellular Space (drug effects, metabolism)
• Immunity (drug effects)
• Interleukin-1beta (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Pneumonia (complications, immunology, metabolism, pathology)
• Purinergic P2X Receptor Antagonists (pharmacology)
• Pyroglyphidae (physiology)
• Receptors, Purinergic P2X7 (deficiency, metabolism)
• Th2 Cells (drug effects, immunology)
• Up-Regulation (drug effects)