Platelets engage mast cells in a bilateral IL-33-driven feed-forward loop.

Platelets amplify type 2 inflammation (T2I) through incompletely understood mechanisms. Depletion of platelets markedly attenuated mast cell (MC) activation in a model of aspirin exacerbated respiratory disease (AERD) that depends on IL-33 and cysteinyl leukotrienes (cysLTs). We demonstrate an IL-33-driven feed-forward loop between platelets and MCs. IL-33 neutralization prevented increases in cysLTs and CXCL7, a platelet activation marker, in bronchoalveolar lavage (BAL) fluid from AERD-like mice in response to aspirin challenges. BAL fluid concentrations of PGD2 correlated strongly with both CXCL7 and MC tryptase in subjects with severe asthma. Platelets amplified PGD2 and LTC4 productions by IL-33-stimulated mouse bone marrow-derived MCs (BMMCs), which induced release of CXCL7 and expression of CD62P by platelets. Deletions of MC-specific LTC4 or platelet-specific type 2 cysLT receptor (CysLT2R) completely eliminated both platelet activation and the amplification of PGD2 and LTC4 generation by MCs. Platelet-derived ADP/ATP and MC-associated P2Y1 receptors were essential. These findings identify an innate immune pathway involving MC-platelet interplay that may drive IL-33-dependent immunopathology in asthma.