Agonism of the glutamate receptor GluK2 suppresses dermal mast cell activation and cutaneous inflammation

Activation of dermal mast cells through the Mas-related G-protein-coupled receptor B2 receptor (MrgprB2; MrgprX2 in humans) is a key component of numerous inflammatory skin diseases including dermatitis and rosacea. Sensory neurons actively suppress mast cell activation through the regulated release of glutamate resulting in reduced expression of Mrgprb2 and genes associated with proteins found in granules. To determine whether exogenous glutamate receptor agonism could suppress mast cell function, we determined that mast cells have relatively selective expression of the glutamate receptor GluK2. A GluK2-specific agonist, SYM2081, effectively inhibited mast cell degranulation in response to MrgprB2 agonism in vitro in murine mast cells and human skin explants as well as in vivo, following both intradermal and topical administration in mice. Analyses of transcriptomic datasets from SYM2081 treated mast cells using standard differential expression approaches as well as a novel interpretable machine learning technique revealed a previously unrecognized cellular program coordinately regulated by GluK2 agonism. Notably, GluK2 agonism suppressed the expression of Mrgprb2 and genes associated with proliferation. Suppression of mast cell proliferation by SYM2081 exposure was confirmed based on reduced Ki-67 expression and BrdU incorporation in vitro and in vivo. Finally, pretreatment with SYM2081 significantly reduced skin inflammation in murine dermatitis and rosacea models. Thus, agonism of GluK2 represents a promising approach to suppress mast cell activation and may prove beneficial as therapy for inflammatory diseases in which mast cell activation is pathogenic. Overall design: The goal of this study was to determine the glutamate receptor expression on mast cells, and if glutamate receptor agonism could modulate mast cell activation and skin inflammation To characterize the transcriptomic changes within MC following GluK2 modulation, we performed bulk RNA sequencing on PCMC treated with vehicle, glutamate, and SYM2081 as well as sorted dermal MCs from MrgprDDTR mice.