Ction such as in the Pseudomonas aeruginosa infection model [17]. In the

Ction such as in the Pseudomonas aeruginosa infection model [17]. In the present study, we observed a lower infiltration of DCs, CD4+ and CD8+ T cells in the BALFs of P2Y22/2 mice compared to those of P2Y2+/+ mice. This lack of infiltration can be correlated to the data of Muller and colleagues demonstrating that P2Y2R is ?involved in the recruitment of DCs in the lungs [23]. IL-12 level was quantified in the BALFs of P2Y2+/+ and P2Y22/2 PVMinfected mice and was significantly lower in P2Y2-deficient mice at days 8 and 10 post-infection. DCs are one primary producer of IL12 which induces the proliferation of NK, T cells, DCs and macrophages, the production of IFN-c and increased cytotoxic activity of these cells. IL-12 also promotes the polarization of CD4+ T cells to the Th1 phenotype involved against viral infection. Higher IL-6 level observed in P2Y22/2 BALFs could also reflect a defective Th1 response in these mice. It was indeed shown that IL-6 production by pulmonary dendritic cells impedes Th1 immune responses [24]. The absence of P2Y2 receptor and the Conduritol B epoxide chemical information reduced level of its ligand ATP which are involved in DC recruitment in the lungs [23] could explain lower DC infiltration observed in P2Y22/2 lungs. Lower ATP level in P2Y22/2 lung could be explained by P2Y2-mediated ATP release. P2Y2 activation was shown to open pannexin-1 channels forming non-selective pores permeable to ions and large molecules such as ATP in rat carotid body cells [25]. Lower DC and T lymphocyte infiltration could also have been related to reduced level of DC-recruiting chemokines. A comparative gene profiling analysis of P2Y2+/+ and P2Y22/2 PVM-infected lungs focused on inflammatory genes revealed the down-regulation ofProtective Role of P2Y2 against Pneumonia VirusBRAK (CXCL-14) in P2Y22/2 lungs. The quantification of DC recruiters IP-10 (CXCL10), MIP-3a (CCL20) and BRAK (CXCL14) by ELISA or qPCR in P2Y2+/+ and P2Y22/2 BALFs confirmed lower expression of BRAK at day 10 post-infection in the P2Y22/2 BALFs compared to P2Y2+/+ BALFs. Interestingly, BRAK is a potent chemoattractant and activator of dendritic cells [26]. It has also an CUDC-907 site ability to block endothelial cell chemotaxis resulting in the inhibition of angiogenesis [27]. CXCL14 is constitutively and highly expressed in many normal tissues, where its source is thought to be fibroblasts [28] and epithelial cells [29] which both express P2Y2 receptors. Reduced DC infiltration in P2Y22/2 PVM-infected lungs could result from a defect in both direct nucleotide-driven and BRAK-mediated DC chemotaxis. Recruitment of T cells was also affected in PVM-infected P2Y2deficient mice. Both CD4+ and CD8+ T cells contribute to the clearance of PVM from the lung [11]. Genetically T-cell-deficient or T-cell-depleted mice cannot eliminate PVM. The increased morbidity and mortality of P2Y22/2 mice could be the consequence of a lower viral clearance leading to a more persistent viral load and higher viral titers as observed at daypost-infection in the lungs of P2Y22/2 infected mice. The decreased viral clearance could result from the defective Th1 response to PVM with a lack of DC and T cell infiltration. Additionally, we cannot exclude that P2Y22/2 mice display after 10 days an excessive inflammation with higher neutrophil recruitment compatible with the increase in KC, MIP-2 and IL6, but this could not be efficiently analysed because of their high and rapid mortality. In conclusion, our study reveals that the purinergic P2Y2 r.Ction such as in the Pseudomonas aeruginosa infection model [17]. In the present study, we observed a lower infiltration of DCs, CD4+ and CD8+ T cells in the BALFs of P2Y22/2 mice compared to those of P2Y2+/+ mice. This lack of infiltration can be correlated to the data of Muller and colleagues demonstrating that P2Y2R is ?involved in the recruitment of DCs in the lungs [23]. IL-12 level was quantified in the BALFs of P2Y2+/+ and P2Y22/2 PVMinfected mice and was significantly lower in P2Y2-deficient mice at days 8 and 10 post-infection. DCs are one primary producer of IL12 which induces the proliferation of NK, T cells, DCs and macrophages, the production of IFN-c and increased cytotoxic activity of these cells. IL-12 also promotes the polarization of CD4+ T cells to the Th1 phenotype involved against viral infection. Higher IL-6 level observed in P2Y22/2 BALFs could also reflect a defective Th1 response in these mice. It was indeed shown that IL-6 production by pulmonary dendritic cells impedes Th1 immune responses [24]. The absence of P2Y2 receptor and the reduced level of its ligand ATP which are involved in DC recruitment in the lungs [23] could explain lower DC infiltration observed in P2Y22/2 lungs. Lower ATP level in P2Y22/2 lung could be explained by P2Y2-mediated ATP release. P2Y2 activation was shown to open pannexin-1 channels forming non-selective pores permeable to ions and large molecules such as ATP in rat carotid body cells [25]. Lower DC and T lymphocyte infiltration could also have been related to reduced level of DC-recruiting chemokines. A comparative gene profiling analysis of P2Y2+/+ and P2Y22/2 PVM-infected lungs focused on inflammatory genes revealed the down-regulation ofProtective Role of P2Y2 against Pneumonia VirusBRAK (CXCL-14) in P2Y22/2 lungs. The quantification of DC recruiters IP-10 (CXCL10), MIP-3a (CCL20) and BRAK (CXCL14) by ELISA or qPCR in P2Y2+/+ and P2Y22/2 BALFs confirmed lower expression of BRAK at day 10 post-infection in the P2Y22/2 BALFs compared to P2Y2+/+ BALFs. Interestingly, BRAK is a potent chemoattractant and activator of dendritic cells [26]. It has also an ability to block endothelial cell chemotaxis resulting in the inhibition of angiogenesis [27]. CXCL14 is constitutively and highly expressed in many normal tissues, where its source is thought to be fibroblasts [28] and epithelial cells [29] which both express P2Y2 receptors. Reduced DC infiltration in P2Y22/2 PVM-infected lungs could result from a defect in both direct nucleotide-driven and BRAK-mediated DC chemotaxis. Recruitment of T cells was also affected in PVM-infected P2Y2deficient mice. Both CD4+ and CD8+ T cells contribute to the clearance of PVM from the lung [11]. Genetically T-cell-deficient or T-cell-depleted mice cannot eliminate PVM. The increased morbidity and mortality of P2Y22/2 mice could be the consequence of a lower viral clearance leading to a more persistent viral load and higher viral titers as observed at daypost-infection in the lungs of P2Y22/2 infected mice. The decreased viral clearance could result from the defective Th1 response to PVM with a lack of DC and T cell infiltration. Additionally, we cannot exclude that P2Y22/2 mice display after 10 days an excessive inflammation with higher neutrophil recruitment compatible with the increase in KC, MIP-2 and IL6, but this could not be efficiently analysed because of their high and rapid mortality. In conclusion, our study reveals that the purinergic P2Y2 r.