Leukotriene D₄ paradoxically limits LTC₄-driven platelet activation and lung immunopathology.

Abstract

The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C₄ (LTC₄), LTD₄, and LTE₄, have different biologic half-lives, cellular targets, and receptor specificities. CysLT₂R binds LTC₄ and LTD₄in vitro with similar affinities, but it displays a marked selectivity for LTC₄in vivo. LTC₄, but not LTD₄, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT₂R-mediated, platelet- and IL-33-dependent pathway. We sought to determine whether LTD₄ functionally antagonizes LTC₄ signaling at CysLT₂R. We used 2 different in vivo models of CysLT₂R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets. LTC₄-induced CD62P expression; HMGB1 release; and secretions of thromboxane A₂, 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 on CysLT₁R. Inhaled LTD₄ blocked LTC₄-mediated potentiation of ovalbumin-induced eosinophilic inflammation; recruitment of platelet-adherent eosinophils; and increases in IL-33, IL-4, IL-5, and IL-13 levels in lung tissue. In contrast, the effect of 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 that in aspirin-exacerbated respiratory disease, completely blocked the physiologic response to subsequent lysine-aspirin inhalation challenges, as well as increases in levels of IL-33, type 2 cytokines, and biochemical markers of mast cell and platelet activation. The conversion of LTC₄ to LTD₄ may limit the duration and extent of potentially deleterious signaling through CysLT₂R, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.