Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism.

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 Leukotriene C₄ (LTC₄) induces surface HMGB1 expression by mouse platelets in a CysLT₂R-dependent manner. Blockade of 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 duanyu1648 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 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or duanyu1648 may be useful to treat AERD and other disorders associated with type 2 immunopathology.

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