Environmental toxicant exposure induces IgE-independent mast cell degranulation through the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) 3133

Abstract Description It has been recognized that the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) receptor contributes to IgE-independent mast cell activation pathways. This orphan receptor can be activated by a numerous array of ligands, many of which are still unknown. Notably, with the rise in global air pollution, the list of potential pseudo-allergic triggers is growing and includes exposure to many environmental toxicants, such as formaldehyde (FA) and amorphous silica nanoparticles (SiNPs). Utilizing human mast cells (HMC-1.2), the capability of FA and SiNP exposure to induce mast cell activation and degranulation was tested. MRGPRX2-specific activity was determined using pretreatment with QWF, a MRGPRX2 inhibitor, and results were compared to responses induced by the MRGPRX2-specific agonist, compound 48/80. Mast cell activation, determined by calcium flux, was induced by both FA and SiNP exposure to a similar degree as compound 48/80. Degranulation, analyzed by measuring β-hexosaminidase activity and lysosomal-associated membrane glycoprotein 2 (LAMP2) expression, was significantly increased following FA and SiNP exposure. Importantly, QWF pretreatment showed complete inhibition for mast cell activation by FA and SiNPs. These findings indicate that MRGPRX2 is, in part, involved in FA and SiNP induced mast cell activation, contributing valuable insight for potential therapeutic targets. Funding Sources Supported by NIH R01ES019311; T32ES029074 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)