1. Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism
- Author
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Joshua A. Boyce, Kathleen M. Buchheit, Tanya M. Laidlaw, Juying Lai, Denise Garofalo, Howard R. Katz, Yoshihide Kanaoka, Nora A. Barrett, Tao Liu, and Chunli Feng
- Subjects
Blood Platelets ,Male ,0301 basic medicine ,Leukotrienes ,Receptor for Advanced Glycation End Products ,Immunology ,chemical and pharmacologic phenomena ,HMGB1 ,Article ,RAGE (receptor) ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Immunology and Inflammation ,0302 clinical medicine ,Immunopathology ,Animals ,Humans ,Immunology and Allergy ,Platelet ,Mast Cells ,Platelet activation ,HMGB1 Protein ,Receptor ,Lung ,Cells, Cultured ,Prostaglandin-E Synthases ,Mice, Knockout ,Receptors, Leukotriene ,biology ,Leukotriene C4 ,Chemistry ,type 2 immunity ,asthma ,Biological Sciences ,Interleukin-33 ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Cysteinyl leukotriene receptor 2 ,biology.protein ,Asthma, Aspirin-Induced ,Signal Transduction ,030215 immunology - Abstract
Cysteinyl leukotrienes (cysLTs) facilitate eosinophilic mucosal type 2 immunopathology, especially in aspirin-exacerbated respiratory disease (AERD), by incompletely understood mechanisms. We now demonstrate that platelets, activated through the type 2 cysLT receptor (CysLT2R), cause IL-33-dependent immunopathology through a rapidly inducible mechanism requiring the actions of high mobility box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Leukotriene C4 (LTC4) induces surface HMGB1 expression by mouse platelets in a CysLT2R-dependent manner. Blockade of RAGE and neutralization of HMGB1 prevent LTC4-induced platelet activation. Challenges of AERD-like Ptges−/− mice with inhaled lysine aspirin (Lys-ASA) elicit LTC4 synthesis and cause rapid intrapulmonary recruitment of platelets with adherent granulocytes, along with platelet- and CysLT2R-mediated increases in lung IL-33, IL-5, IL-13, and bronchoalveolar lavage fluid HMGB1. The intrapulmonary administration of exogenous LTC4 mimics these effects. Platelet depletion, HMGB1 neutralization, and pharmacologic blockade of RAGE eliminate all manifestations of Lys-ASA challenges, including increase in IL-33, mast cell activation, and changes in airway resistance. Thus, CysLT2R signaling on platelets prominently utilizes RAGE/HMGB1 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunopathology.
- Published
- 2019