Cutting Edge: Leukotriene C4 Activates Mouse Platelets in Plasma Exclusively through the Type 2 Cysteinyl Leukotriene Receptor

Leukotriene C-4 (LTC4) and its extracellular metabolites, LTD4 and LTE4, mediate airway inflammation. They signal through three specific receptors (type 1 cys-LT receptor [CysLT(1)R], CysLT(2)R, and GPR99) with overlapping ligand preferences. In this article, we demonstrate that LTC4, but not LTD4 or LTE4, activates mouse platelets exclusively through CysLT(2)R. Platelets expressed CysLT(1)R and CysLT(2)R proteins. LTC4 induced surface expression of CD62P by wildtype mouse platelets in platelet-rich plasma (PRP) and caused their secretion of thromboxane A(2) and CXCL4. LTC4 was fully active on PRP from mice lacking either CysLT(1)R or GPR99, but completely inactive on PRP from CysLT(2)R-null (Cysltr2(-/-)) mice. LTC4/CysLT(2)R signaling required an autocrine ADP-mediated response through P2Y(12) receptors. LTC4 potentiated airway inflammation in a platelet-and CysLT(2)R-dependent manner. Thus, CysLT(2)R on platelets recognizes LTC4 with unexpected selectivity. Nascent LTC4 may activate platelets at a synapse with granulocytes before it is converted to LTD4, promoting mediator generation and the formation of leukocyte-platelet complexes that facilitate inflammation.