mMrgprA3/mMrgprC11/hMrgprX1: Potential therapeutic targets for allergic contact dermatitis-induced pruritus in mice and humans

Background Although the Mas-related G-protein-coupled receptors (Mrgprs) play essential roles in itch detection, their contribution to allergic contact dermatitis (ACD)-associated itch remains unclear. Objectives To investigate whether Mrgprs are involved in ACD and whether Mrgprs can be identified as potential therapeutic targets. Methods Mrgpr-cluster Delta(-/-) mice and human MrgprX1 (hMrgprX1) transgenic mice were used to evaluate the function of Mrgprs in oxazolone-induced ACD. Results Utilizing an ACD model, we found that Mrgpr-cluster Delta(-/-) mice display significantly reduced pruritus. Among 12 Mrgprs deleted in Mrgpr-cluster Delta(-/-) mice, the expression of MrgprC11 and MrgprA3 was significantly increased in the ACD model, which also innervated the skin and spinal cord at higher-than-normal densities. The proportions of dorsal root ganglia neurons responding to bovine adrenal medulla peptide 8-22 and chloroquine were also remarkably increased in the ACD model, resulting in enhanced itch behaviour. To study the function of human Mrgprs in ACD-induced itch, we used hMrgprX1 transgenic mice, which rescued the severe itch defect of Mrgpr-cluster Delta(-/-) mice in the ACD model. Remarkably, pharmacological blockade of hMrgprX1 significantly attenuates ACD itch in hMrgprX1 transgenic mouse. Conclusions Our study provides the first evidence that Mrgprs are involved in ACD-induced chronic itch, which provides new avenues for itch management in ACD.

Automated summary

This study provides the first evidence that Mrgprs are involved in ACD-induced chronic itch, with increased expression of MrgprC11 and MrgprA3 in the ACD model. Pharmacological blockade of hMrgprX1 in transgenic mice also significantly attenuated ACD itch.