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RATIONALE: Cysteinyl leukotrienes (cysLTs) act at both structural and hematopoietic cells to facilitate mucosal type 2 (eosinophilic) immunopathology. LTC 4 acts at platelet-associated CysLT2R to upregulate lung endothelial adhesion receptors essential for antigen-induced eosinophil recruitment. Because platelets can release high mobility box 1 (HMGB1), a known inducer of type 2 immunopathology and endothelial activation, we sought to determine whether cysLTs elicit allergic lung inflammation through HMGB1 and the receptor for advanced glycation end products (RAGE). METHODS: Ovalbumin-sensitized mice were challenged with aerosolized LTC 4 for lung inflammation determination. Mouse platelets were stimulated with LTC 4 analyzed for surface CD62P and HMGB1 by FACS analysis. RESULTS: LTC 4 , but not its metabolites LTD 4 or LTE 4 , induced surface expression of HMGB1 by mouse platelets in a CysLT2R-dependent manner. Blockade of RAGE prevented LTC 4-induced platelet activation ex vivo. LTC 4 challenge on ovalbumin-sensitized WT mice showed increased HMGB1, CXCL7, TXB 2 in BAL. Neutralization of HMGB1 with a monoclonal Ab or blockade of RAGE with the selective antagonist prevented LTC 4-induced increases in airway eosinophilia, platelet activation, and IL-5/IL-13 production. Depletion of platelets eliminated the LTC 4-induced increase in HMGB1. Short-term HMGB1 neutralization prevented cysLT-driven reactions to inhaled lysine-aspirin in Ptges-/mice, which exhibit a phenotype of aspirin exacerbated respiratory disease. CONCLUSIONS: Platelet HMGB1 activates platelets in an autocrine loop that can drive type 2 lung immunopathology and aspirin sensitivity downstream of cysLT release. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunpathology.