Mast cell specific receptor Mrgprb2/X2 regulates bladder immunity during urinary tract infections

Urinary tract infections (UTIs) are the most common bacterial infections in women. During UTI, the host mounts a rapid immune response to clear the invading pathogen from the bladder. Mast cells are tissue resident immune cells that are found in the bladder lamina propria and can serve as first responders to bacterial infections. Here, we investigated the role of the mouse mast cell receptor Mrgprb2 and its human homologue MRGPRX2 in UTI. During acute UTI, Mrgprb2 is activated by the antimicrobial peptide cathelicidin and mediates mast cell degranulation. Using Mrgprb2 knockout mice, we demonstrated that Mrgprb2 promotes immune cell recruitment and amplifies inflammation, leading to epithelial damage and increased bacterial burden. Pharmacological inhibition of Mrgprb2 with its antagonist osthole improved infection outcomes. Using a humanized MRGPRX2 knock-in mouse in which Mrgprb2 is replaced by human MRGPRX2, we show conserved function of the mouse and human receptors in the bladder. Our findings identify human mast cell receptor MRGPRX2 as a potential therapeutic target to improve patient outcomes during UTI.