Alveolar macrophage P2Y6 receptor signaling blocks adaptive type 2 allergic inflammation by enhancing IL-12 production by alveolar macrophage during the innate phase of house dust mite (Df) exposure. However, the mechanisms through which alveolar macrophage P2Y6 receptors potentiate IL-12 production and reinforce the innate immune response are unknown. We studied signaling downstream of P2Y6 receptor in bone marrow-derived macrophages (BMMs) and ex vivo alveolar macrophages, and performed in vivo alveolar macrophage transplantation with wild-type and Nfatc2 gene deleted mice in P2Y6 deleted recipient mice. Primed UDP/P2Y6 signaling potentiated Df-induced IL-12 production in BMMs, and this potentiation was significantly blocked by calcineurin inhibitors. Immunofluorescent staining of BMMs showed UDP specifically induced nuclear translocation of NFATC2, but not NFATC1 or NFATC3. Pulmonary transplantation of wild-type but not Nfatc2 gene deleted BMMs restored the decreased Df-induced IL-12 production in P2Y6 gene deleted mice. Nfatc2 gene deleted mice displayed increased type 2 inflammation in response to Df challenge, similar to P2Y6 gene deleted mice. We concluded that alveolar macrophage P2Y6 receptor signaling specifically induces NFATC2 activation to potentiate protective IL-12 production, which is a potential mechanism that protect against inappropriate type 2 immune responses.