GluK2 agonism suppresses dermal mast cell activation and proliferation

Abstract

Abstract It has been recently appreciated that mast cells respond to glutamate in the context of neural transimtter release and tissue injuries. However, the precise subtype of glutamate receptor expressed on dermal mast cells at steady states and its function remain to be elucidated. Herein, we identified the kainate receptor GluK2/KA2 as the predominant glutamate receptor expressed on dermal MCs at the mRNA and protein level. GluK2 agonists such as glutamic acid and kainic acid suppressed the activation of cultured peritoneal mast cells (PMCs) in response to MrgprB2 ligand compound 48/80, corroborating a previously demonsrated neuroimmune pathway. The GluK2 selective agonist SYM2081 downregulated MrgprB2 expression and inhibited compound 48/80-mediated PMC activation. SYM2081 suppresed various mast cell-dependent inflammation models in vivo, such croton oil-induced irritant dermatitis, DNFB contact hypersensitivity, and LL-37 induced rosacea. The suppressive effect of SYM2081 on mast cells holds true in a model of human skin explants as well. Transcriptomic analysis revealed that GluK2 agonism suppresses proliferation pathways in mast cells and downregulates granule content synthesis, such as mast cell chymase 1. Together, this study identified a previously unappreciated glutamate receptor on dermal mast cells and raised the interesting posibility of using selective GluK2 agonists to as a therapeutic agent for inflammatory conditions where MCs play a key role in the pathogenesis.