Abstract
ATP released in the early inflammatory processes acts as a danger signal by binding to purinergic receptors expressed on immune cells. A major contribution of the P2Y(2) receptor of ATP/UTP to dendritic cell function and Th2 lymphocyte recruitment during asthmatic airway inflammation was previously reported. We investigated here the involvement of P2Y(2) receptor in lung inflammation initiated by pneumonia virus of mice infection. We demonstrated that P2Y(2) (-/-) mice display a severe increase in morbidity and mortality rate in response to the virus. Lower survival of P2Y(2) (-/-) mice was not significantly correlated with excessive inflammation despite the higher level of neutrophil recruiters in their bronchoalveolar fluids. Interestingly, we observed reduced ATP level and lower numbers of dendritic cells, CD4(+) T cells and CD8(+) T cells in P2Y(2) (-/-) compared to P2Y(2) (+/+) infected lungs. Lower level of IL-12 and higher level of IL-6 in bronchoalveolar fluid support an inhibition of Th1 response in P2Y(2) (-/-) infected mice. Quantification of DC recruiter expression revealed comparable IP-10 and MIP-3α levels but a reduced BRAK level in P2Y(2) (-/-) compared to P2Y(2) (+/+) bronchoalveolar fluids. The increased morbidity and mortality of P2Y(2) (-/-) mice could be the consequence of a lower viral clearance leading to a more persistent viral load correlated with the observed higher viral titer. The decreased viral clearance could result from the defective Th1 response to PVM with a lack of DC and T cell infiltration. In conclusion, P2Y(2) receptor, previously described as a target in cystic fibrosis therapy and as a mediator of Th2 response in asthma, may also regulate Th1 response protecting mice against lung viral infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Bronchoalveolar Lavage Fluid / chemistry
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Bronchoalveolar Lavage Fluid / immunology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / virology
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Chemokine CCL20 / genetics
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Chemokine CCL20 / immunology
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Chemokine CXCL10 / genetics
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Chemokine CXCL10 / immunology
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Chemokines, CXC / genetics
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Chemokines, CXC / immunology
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Dendritic Cells / immunology
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Dendritic Cells / virology
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Female
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Gene Expression
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / virology
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Lung / immunology
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Lung / metabolism*
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Lung / virology
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Mice
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Mice, Knockout
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Murine pneumonia virus / immunology*
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Neutrophils / immunology
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Neutrophils / virology
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Pneumonia, Viral / immunology
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Pneumonia, Viral / metabolism*
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Pneumonia, Viral / virology
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Pneumovirus Infections / immunology
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Pneumovirus Infections / metabolism*
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Pneumovirus Infections / virology
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Receptors, Purinergic P2Y2 / deficiency
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Receptors, Purinergic P2Y2 / genetics
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Receptors, Purinergic P2Y2 / immunology*
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Survival Rate
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Th1 Cells / immunology
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Th1 Cells / virology
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Th2 Cells / immunology
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Th2 Cells / virology
Substances
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CXCL14 protein, mouse
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Chemokine CCL20
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Chemokine CXCL10
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Chemokines, CXC
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Cxcl10 protein, mouse
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Interleukin-6
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Receptors, Purinergic P2Y2
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Interleukin-12
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Adenosine Triphosphate
Grants and funding
This work was supported by an Action de Recherche Concertée of the Communauté Française de Belgique, an Interuniversity Attraction Pole grant from the Politique Scientifique Fédérale (IAP-P6/30), Prime Minister's Office, Federal Service for Science, Technology and Culture, by grants of the Fonds de la Recherche Scientifique Médicale (F.R.S.M.), the Fonds d'Encouragement à la Recherche (F.E.R.), the Fonds Emile DEFAY, the Fonds de la Recherche Scientifique Médicale of Belgium, the Walloon Region (Programme d'Excellence CIBLES), and the LifeSciHealth programme of the European Community (grant LSHB-2003-503337). D. Communi is Senior Research Associate of the Fonds National de la Recherche Scientifique (F.N.R.S.), Belgium. G. Vanderstocken is supported by the F.N.R.S./FRIA and the Fonds Van Buuren, Belgium. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.