PMX-53 as a Dual CD88 Antagonist and an Agonist for Mas-Related Gene 2 (MrgX2) in Human Mast Cells

Abstract

Human mast cells express the G protein coupled receptor (GPCR) for C5a (CD88). Previous studies indicated that C5a could cause mast cell degranulation, at least in part, via a mechanism similar to that proposed for basic neuropeptides such as substance P, possibly involving Mas-related gene 2 (MrgX2). We therefore sought to more clearly define the receptor specificity for C5a-induced mast cell degranulation. We found that LAD2, a human mast cell line, and CD34

Mas-related Gene X2 (MrgX2) Is a Novel G Protein-coupled Receptor for the Antimicrobial Peptide LL-37 in Human Mast Cells

“…It is noteworthy that mast cells are the only known cells outside the dorsal ganglia that express MrgX2 (28). Furthermore, this receptor is activated by basic peptides (27,28) Given that LL-37 displays basic properties, we hypothesized that it could activate mast cells via MrgX2. Although LAD2 cells endogenously express MrgX2, an immature human mast cell line, HMC-1 cells do not express functional receptors (27).…”

“…Furthermore, this receptor is activated by basic peptides (27,28) Given that LL-37 displays basic properties, we hypothesized that it could activate mast cells via MrgX2. Although LAD2 cells endogenously express MrgX2, an immature human mast cell line, HMC-1 cells do not express functional receptors (27). By contrast both cell lines express GPCR for C3a (C3aR) (43).…”

“…Stable Transfection of RBL-2H3 and HMC-1 Cells-RBL-2H3 cells stably expressing MrgX1 and MrgX2 were generated as described previously (27,36). For HMC-1 cells, 2 ϫ 10 6 cells were transfected with plasmids encoding HA-tagged MrgX2 using the Amaxa nucleofector device and Amaxa kit V according to the manufacturer's protocol.…”

“…Using shRNA-mediated knockdown of MrgX2 in human mast cells, we provide the novel finding that LL-37 causes sustained Ca 2ϩ mobilization and degranulation via MrgX2. Moreover, using transfected mast cell lines that do not natively express MrgX2 (27), we demonstrate that LL-37 promotes chemotaxis and induces chemokine, CCL4 via MrgX2.…”

“…Interestingly, a subgroup of these receptors (MrgX1-MrgX4) are expressed in human but not in murine neurons (24,26). Recent studies have shown that MrgX2 is also expressed in human mast cells and activated by basics peptides (27,28). Given that LL-37 also displays basic properties, we hypothesized that it activates human mast cells via MrgX2.…”