MRGPRX2 antagonist treatment prevents inflammation and disease in a mouse model of atopic dermatitis

The Mas-related G-protein-coupled receptor X2 is a promiscuous receptor expressed on mast cells that mediates IgE-independent mast cell activation and degranulation in response to a variety of diverse agonists and has been implicated in numerous inflammatory conditions, including atopic dermatitis (AD). We investigated whether the small-molecule Mas-related G-protein-coupled receptor X2 antagonist INCB000262 improves disease phenotype in the house dust mite + Staphylococcus aureus enterotoxin type B (HDM+SEB) mouse model of AD and further characterized mast cell-mediated aspects of disease. Mas-related G-protein-coupled receptor X2 knock-in mice were sensitized to HDM+SEB and orally dosed once daily with either vehicle or INCB000262 for 4 weeks, and efficacy and skin transcriptional changes were evaluated. INCB000262 attenuated HDM+SEB-induced AD in vivo, with improvements observed in skin thickness, transepidermal water loss, tissue weight, and overall clinical score. In addition, transcriptome changes induced by HDM+SEB exhibited a mast cell activation signature consistent with human AD lesional skin, which was attenuated by antagonist treatment. Overall, INCB000262, a Mas-related G-protein-coupled receptor X2 antagonist, attenuated HDM+SEB-induced AD disease phenotypes and mast cell-associated transcriptional changes, supporting further evaluation of INCB000262 as an oral treatment for AD and other mast cell-mediated diseases.