β-defensins activate human mast cells via Mas-related Gene-X2: cross-regulation by LPS (P4179)

Abstract

Abstract Human β-defensins (hBDs) stimulate degranulation in rat peritoneal mast cells and cause increased vascular permeability in wild-type but not mast cell-deficient rats. Here, we sought to determine if hBDs activate murine and human mast cells and to delineate the mechanisms of their regulation. hBD2 and hBD3 did not induce degranulation in murine peritoneal or bone marrow-derived mast cells in vitro and had no effect on vascular permeability in vivo. By contrast, they induced sustained Ca2+ mobilization and substantial degranulation in human mast cells with hBD3 being more potent. While human mast cells endogenously express G protein coupled receptor (GPCR); Mas-related gene X2 (MrgX2), murine mast cells and rat basophilic leukemia, RBL-2H3 cells do not. Silencing the expression of MrgX2 in human mast cells inhibited hBD2/3-induced degranulation and ectopic expression of MrgX2 in RBL-2H3 cells restored these responses. Interestingly, lipopolysaccharide (LPS) inhibited hBD3 but not hBD2-induced Ca2+ mobilization and degranulation. Thus, hBDs activate human mast cells via MrgX2 and that the resistance of murine mast cells likely reflects the absence of this GPCR. Furthermore, the ability of LPS to inhibit hBD3/MrgX2-mediated mast cell activation provides a novel complexity of the role of mast cells in host defense and inflammation.