Identification of lysophosphatidylserine receptor P2Y10 as a novel G-protein coupled receptor mediating eosinophil degranulation

Abstract

Abstract P2Y10, along with GPR34 and GPR174, is a G protein-coupled receptor that is activated by lysophosphatidylserine (LysoPS), and its expression and function have not yet been described. We have previously shown that P2Y10 is one of the highly upregulated genes at the late differentiation stage during in vitro eosinophilopoiesis. In the present study, we examine the expression and functions of P2Y10 in human eosinophils. P2Y10 is increasingly expressed, as cord blood (CB) CD34+ cells differentiate toward eosinophils. Analysis of its expression in peripheral blood (PB) leukocytes shows that P2Y10 is the most highly expressed in the granulocytes among the major leukocytes in numbers, including lymphocytes, monocytes, and granulocytes. Importantly, PB eosinophils express this receptor much more strongly than PB neutrophils. In contrast, GPR34 and GPR174 are negligible on PB eosinophils, while being comparable to P2Y10 in PB neutrophils. LysoPS activates CB eosinophils to induce a robust ERK phosphorylation as profoundly as IL-5. LysoPS is able to trigger degranulation of eosinophil cationic protein (ECP) in PB eosinophils, and its capability of degranulation is significantly blocked by inhibitors of signaling or receptor molecules including ERK, TACE, and EGFR. Taken together, our data suggest that LysoPS provokes a proinflammatory functions of eosinophils likely through P2Y10, proposing P2Y10 as a potential therapeutic target to control eosinophil-associated diseases.