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

J Allergy Clin Immunol. 2021 Jul;148(1):195-208.e5. doi: 10.1016/j.jaci.2020.10.041. Epub 2020 Dec 4.

Abstract

Background: 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.

Objective: We sought to determine whether LTD4 functionally antagonizes LTC4 signaling at CysLT2R.

Methods: We used 2 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, 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.

Conclusion: 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.

Keywords: AERD; CysLT(2)R; Platelets; eosinophils; leukotrienes; mast cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / immunology
  • Blood Platelets / immunology*
  • Cysteine / immunology
  • Cytokines / immunology
  • Leukotriene C4 / immunology*
  • Leukotriene D4 / immunology*
  • Leukotriene E4 / immunology
  • Leukotrienes / immunology
  • Lung / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Platelet Activation / immunology*
  • Pulmonary Eosinophilia / immunology
  • Receptors, Leukotriene / immunology

Substances

  • Cytokines
  • Leukotrienes
  • Receptors, Leukotriene
  • cysteinyl-leukotriene
  • Leukotriene C4
  • Leukotriene D4
  • Leukotriene E4
  • Cysteine