Leukotriene D4 Paradoxically Limits LTC4 Driven Platelet Activation and Lung Immunopathology.

Abstract Background The three cysteinyl leukotrienes (cysLTs), (LT)C4, LTD4, and LTE4, have different biological half-lives, cellular targets, and receptor specificities. CysLT2R binds LTC4 and LTD4 in vitro with similar affinities, but displays a marked selectivity for LTC4 in vivo. LTC4, but not LTD4, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT2R-mediated, platelet- and interleukin-33 dependent pathway. Objective We sought to determine whether LTD4 functionally antagonize LTC4 signaling at CysLT2R. Methods We employed two different in vivo models of CysLT2R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets. Results LTC4-induced CD62P expression, HMGB1 release, and secretions of thromboxane A2 (TXA2), CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLT2R antagonist and inhibited by LTD4. These effects did not depend CysLT1R. Inhaled LTD4 blocked LTC4-mediated, potentiation of ovalbumin (OVA)-induced eosinophilic inflammation, recruitment of platelet-adherent eosinophils, and increases in IL-33, IL-4, IL-5, and IL-13 in the lung tissue. In contrast, administration of LTE4, the preferred ligand for CysLT3R, was additive with LTC4. The administration of LTD4 to Ptges-/- mice, which display enhanced LTC4 synthesis similar to aspirin exacerbated respiratory disease (AERD), completely blocked the physiologic response to subsequent lysine-aspirin inhalation challenges, as well as increases in IL-33, type 2 cytokines, and biochemical markers of mast cell and platelet activation. Conclusion The conversion of LTC4 to LTD4 may limit the duration and extent of potentially deleterious signaling through CysLT2R, and may contribute to the therapeutic properties of therapeutic desensitization to aspirin in AERD.