Leukotriene E4–induced pulmonary inflammation is mediated by the P2Y12 receptor

Abstract

Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition between radiolabeled ADP and unlabeled LTE4 but not for direct binding of LTE4, suggesting that P2Y12 complexes with another receptor to recognize LTE4. Administration of LTE4 to the airways of sensitized mice potentiates eosinophilia, goblet cell metaplasia, and expression of interleukin-13 in response to low-dose aerosolized allergen. These responses persist in mice lacking both CysLT1R and CysLT2R but not in mice lacking P2Y12 receptors. The effects of LTE4 on P2Y12 in the airway were abrogated by platelet depletion. Thus, the P2Y12 receptor is required for proinflammatory actions of the stable abundant mediator LTE4 and is a novel potential therapeutic target for asthma.

Prostaglandin E2deficiency causes a phenotype of aspirin sensitivity that depends on platelets and cysteinyl leukotrienes

“…Oral administration of zileuton to subjects with AERD blocked the release of tryptase into the nasal lavage fluid following intranasal Lys-ASA challenge (50). MCs express all of the known CysLTRs (14)(15)(16)51), and blockade of CysLT 1 R with montelukast mirrored the effect of zileuton on the release of MC activation products in our study. Thus, AERD involves a prominent autocrine and/or paracrine signaling loop in which cysLTs promote MC activation.…”

P2 receptors and platelet function

“…They are necessary for lung leukocyte recruitment in a murine model of allergic inflammation, and plateletleukocyte aggregates are formed in circulating blood of patients with asthma after allergen exposure [141]. It has been reported that the P2Y 12 receptor is required for proinflammatory actions of the stable abundant mediator LTE4 in allergic asthma and has been suggested to be a novel potential therapeutic target for asthma [142]. The specific contribution of the platelet P2 receptors in this disease warrants further studies as the P2Y 1 receptor has also been proposed to have a role in airways inflammation [143].…”

The platelet P2 receptors in inflammation

“…The greater specificity of the mannitol test for detecting changes in airway hyper-responsiveness in asthma patients is likely explained by the fact that it mimics the normal pathophysiology of bronchial asthma, causing the release of various mediators of bronchoconstriction (76). Although the results of this study cannot clarify whether the effect of prasugrel was mediated by its interaction with P2Y 12 on platelets or other cells, the former hypothesis is supported by the results of experimental studies that demonstrated the important role of platelet P2Y 12 in the recruitment of inflammatory cells in lungs of sensitized mice challenged with cysteinyl-LT (70,71). Moreover, due to the very short half-life of the active metabolite of prasugrel, inhibition of P2Y 12 on nucleated cells, such as leukocytes, would likely be very short lived and probably insufficient to exert any clinically relevant effect (77).…”

“…However, more recently GPR99 was identified as the elusive receptor for LTE 4 (67). Moreover, studies that demonstrated the important role played by platelet P2Y 12 in LTE 4 -or LTC 4 -induced enhanced recruitment of inflammatory cells in the lungs of sensitized mice failed to show that the CysLT interact directly with the platelet P2Y 12 , which might therefore play an indirect, albeit important role in the process (63,70,71).…”