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Leukotriene D4 paradoxically limits LTC4-driven platelet activation and lung immunopathology
Tao Liu1, Nora A Barrett2, Jun Nagai2
1Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Mass; Jeff and Penny Vinik Center for Allergic Disease Research, Boston, Mass.
The Journal of Allergy and Clinical Immunology
|December 7, 2020
Summary
Leukotriene D4 (LTD4) inhibits cysteinyl leukotriene receptor 2 (CysLT2R) signaling, preventing allergic inflammation. This conversion of LTD4 from LTC4 may explain aspirin desensitization benefits in respiratory diseases.
Area of Science:
- Immunology
- Pharmacology
- Respiratory Medicine
Background:
- Cysteinyl leukotrienes (cysLTs) like LTC4, LTD4, and LTE4 have distinct biological roles.
- CysLT2R selectively binds LTC4 in vivo, mediating platelet and IL-33 dependent pulmonary eosinophilia.
- The interaction between LTC4 and LTD4 at CysLT2R was not fully understood.
Purpose of the Study:
- To investigate if LTD4 antagonizes LTC4 signaling at CysLT2R.
- To explore the role of LTD4 in CysLT2R-mediated immunopathology.
Main Methods:
- Utilized two in vivo models of CysLT2R-dependent immunopathology.
- Performed ex vivo activation of mouse and human platelets.
- Administered inhaled LTD4 and LTE4 in mouse models.
Main Results:
- LTD4 inhibited LTC4-induced platelet activation markers (CD62P, HMGB1, Thromboxane A2, CXCL7, IL-33) via CysLT2R, independent of CysLT1R.
- Inhaled LTD4 blocked LTC4-driven eosinophilic lung inflammation and associated cytokine increases.
- LTE4 showed additive effects with LTC4, unlike LTD4's inhibitory action.
Conclusions:
- LTD4 acts as a functional antagonist of LTC4 at CysLT2R.
- The conversion of LTC4 to LTD4 may limit CysLT2R signaling duration and extent.
- This antagonism might contribute to aspirin desensitization in aspirin-exacerbated respiratory disease.
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