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

BACKGROUND

The 3 cysteinyl leukotrienes (cysLTs), leukotriene (LT) C (LTC), LTD, and LTE, have different biologic half-lives, cellular targets, and receptor specificities. CysLTR binds LTC and LTDin vitro with similar affinities, but it displays a marked selectivity for LTCin vivo. LTC, but not LTD, strongly potentiates allergen-induced pulmonary eosinophilia in mice through a CysLTR-mediated, platelet- and IL-33-dependent pathway.

OBJECTIVE

We sought to determine whether LTD functionally antagonizes LTC signaling at CysLTR.

METHODS

We used 2 different in vivo models of CysLTR-dependent immunopathology, as well as ex vivo activation of mouse and human platelets.

RESULTS

LTC-induced CD62P expression; HMGB1 release; and secretions of thromboxane A, CXCL7, and IL-33 by mouse platelets were all were blocked by a selective CysLTR antagonist and inhibited by LTD. These effects did not depend on CysLTR. Inhaled LTD blocked LTC-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, the preferred ligand for CysLTR, was additive with LTC. The administration of LTD to Ptges mice, which display enhanced LTC 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 to LTD may limit the duration and extent of potentially deleterious signaling through CysLTR, and it may contribute to the therapeutic properties of desensitization to aspirin in aspirin-exacerbated respiratory disease.