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.

Cysteinyl leukotriene (cysLT) overproduction is a hallmark of aspirin-exacerbated respiratory disease (AERD), but its mechanism is poorly understood. Because adherent platelets can convert the leukocytederived precursor leukotriene (LT)A 4 to LTC 4 , the parent cysLT, through the terminal enzyme LTC 4 synthase, we investigated the contribution of platelet-dependent transcellular cysLT production in AERD. Nasal polyps from subjects with AERD contained many extravascular platelets that colocalized with leukocytes, and the percentages of circulating neutrophils, eosinophils, and monocytes with adherent platelets were markedly higher in the blood of subjects with AERD than in aspirintolerant controls. Platelet-adherent subsets of leukocytes had higher expression of several adhesion markers than did platelet nonadherent subsets. Adherent platelets contributed more than half of the total LTC 4 synthase activity of peripheral blood granulocytes, and they accounted for the higher level of LTC 4 generation by activated granulocytes from subjects with AERD compared with aspirintolerant controls. Urinary LTE 4 levels, a measure of systemic cysLT production, correlated strongly with percentages of circulating platelet-adherent granulocytes. Because platelet adherence to leukocytes allows for both firm adhesion to endothelial cells and augmented transcellular conversion of leukotrienes, a disturbance in plateletleukocyte interactions may be partly responsible for the respiratory tissue inflammation and the overproduction of cysLTs that characterize AERD. (Blood. 2012;119(16):3790-3798) IntroductionAspirin-exacerbated respiratory disease (AERD) is a distinctive syndrome characterized clinically by a triad of asthma, nasal polyposis, and aspirin sensitivity. It is a chronic inflammatory disease associated with eosinophilic infiltration of respiratory tissues, peripheral eosinophilia, and excessive production of cysteinyl leukotrienes (cysLTs), a class of inflammatory lipid mediators that are thought to contribute to several of the characteristic features of AERD. Individuals with this syndrome account for 4% to 11% of all adult patients with asthma, and for a disproportionate share (ϳ 30%) of patients with severe asthma. 1 The confirmatory diagnostic feature of AERD is an idiosyncratic respiratory reaction, including symptoms of acute bronchoconstriction, nasal congestion, and eye watering, on ingestion of aspirin or another nonselective cyclooxygenase (COX) inhibitor. Despite the strikingly consistent clinical phenotype of AERD, the pathogenesis of the disease remains unclear.CysLTs derive from the metabolism of arachidonic acid by effector cells of the innate immune system. In inflammatory leukocytes (neutrophils, monocytes, eosinophils, mast cells, and basophils), arachidonic acid is oxidized by 5-lipoxygenase (5-LO) to form the unstable intermediate leukotriene (LT)A 4 . 2 In neutrophils, LTA 4 is preferentially hydrolyzed by LTA 4 hydrolase to form LTB 4 , whereas in monocytes, mast cells, eosinophils, and basophils, it i...

Dectin-2 expression on GM-CSF–cultured bone marrow cells is required for the generation of cysteinyl leukotrienes and Th2 cytokines in response to the house dust mite Dermatophagoides farinae in vivo.