Type 6 Purinergic Receptors (P2Y6) Homeostatic Regulation In Allergic Sensitization And Lung Inflammation

RATIONALE: Type 6 purinergic (P2Y₆) receptors are high affinity G protein-coupled receptors (GPCRs) for UDP and the recently identified PGE2-G. We found that P2Y₆ receptors inhibit type 2 immunity in lung allergic inflammation by incompletely understood mechanisms. In this study, we sought to determine the importance of P2Y₆receptors in controlling sensitization or challenge phase by deleting the p2ry6 allele before or after sensitization.

METHODS: p2ry6(flox/flox);rosa26creER/+ and p2ry6(flox/flox);+/+ controls were treated with tamoxifen starting either before the initial sensitization, or immediately following the sensitization. The mice were sensitized with an extract from Dermatophagoides farinae intranasally on days 0-1 and challenged on days 14-15 separately.

RESULTS: Tamoxifen treatment for 5 days decreased the expression of P2Y₆ in the lung, spleen and lymph node by ~90%. When P2Y₆ receptors were deleted before sensitization, Df-treated p2ry6(flox/flox);cre/+ mice exhibited significantly increased eosinophil and neutrophil counts in the BAL fluids compared p2ry6(flox/flox);+/+ controls, as well as increased bronchovascular cellular infiltration. In addition, higher levels of expression of Th2 cytokines and IL-33 mRNA transcripts were present in the lungs of the p2ry6(flox/flox);cre/+ mice than in the lungs of the p2ry6(flox/flox);+/+ controls. However, deleting P2Y₆ after the sensitization phase did not induce the exacerbated lung inflammation and the expression of Th2 cytokines and IL-33 in the lungs of the p2ry6(flox/flox);cre/+ mice tended to be lower than the p2ry6(flox/flox);+/+ controls.

CONCLUSIONS: P2Y₆ receptors expression during the sensitization phase plays a critical role in preventing sensitization to the allergen. P2Y₆ agonist might prove a new therapeutic approach to inhibit the allergic lung inflammation.