Leukotriene D 4 paradoxically limits LTC 4 -driven platelet activation and lung immunopathology.

Background: The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C ₄ (LTC ₄ ), LTD ₄ , and LTE ₄ , have different biologic half-lives, cellular targets, and receptor specificities. CysLT ₂ R binds LTC ₄ and LTD ₄ in vitro with similar affinities, but it displays a marked selectivity for LTC ₄ in vivo. LTC ₄ , but not LTD ₄ , strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLT ₂ R-mediated, platelet- and IL-33-dependent pathway.
Objective: We sought to determine whether LTD ₄ functionally antagonizes LTC ₄ signaling at CysLT ₂ R.
Methods: We used 2 different in vivo models of CysLT ₂ R-dependent immunopathology, as well as ex vivo activation of mouse and human platelets.
Results: LTC ₄ -induced CD62P expression; HMGB1 release; and secretions of thromboxane A ₂ , CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLT ₂ R antagonist and inhibited by LTD ₄ . These effects did not depend on CysLT ₁ R. Inhaled LTD ₄ blocked LTC ₄ -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 LTE ₄ , the preferred ligand for CysLT ₃ R, was additive with LTC ₄ . The administration of LTD ₄ to Ptges ^-/- mice, which display enhanced LTC ₄ 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.
Conclusion: The conversion of LTC ₄ to LTD ₄ may limit the duration and extent of potentially deleterious signaling through CysLT ₂ R, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.
(Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)