Mas-related G-protein coupled receptor X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed in human mast cells that plays an important role in facilitating pseudo-allergic reactions as well exacerbating inflammation during asthmatic and other allergic diseases. Lactic acid, a byproduct of anaerobic glycolysis, is abundantly present in inflamed tissues and has been shown to regulate functions of several immune cells. Because the endogenous ligands for MRGPRX2 (substance P and LL-37) are upregulated during pathologic conditions such as cancer and asthma, the role of lactic acid in regulating mast cells response via MRGPRX2 and MrgprB2, the murine orthologue of the human receptor, is important to define. In this study, lactic acid suppressed both the early (Ca2+ mobilization and degranulation) and late (chemokine/cytokine release) phases of mast cell activation; this data was confirmed in LAD2, human skin and mouse peritoneal mast cells. In LAD2 cells, the reduction in degranulation and chemokine/cytokine production mediated by lactic acid was partially dependent on the pH. In agreement with the in vitro studies, lactic acid also reduced passive systemic anaphylaxis induced by compound 48/80 (a known MRGPRX2/MrgprB2 ligand) and inflammation in an LL-37 induced murine model of rosacea that is dependent on MRGPRB2 expression in skin mast cells. This data suggests that lactic acid may serve to inhibit mast cell-mediated inflammation during asthma and reduce immune response during cancer by affecting mast cell activation through MRGPRX2.
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