Mrgprs activation is required for chronic itch conditions in mice.

Yuyan Zhu,Liang Han,Claire E Hanson,Qin Liu

doi:10.1097/itx.0000000000000009

Yuyan Zhu, Liang Han + Show 2 more

Open Access

https://doi.org/10.1097/itx.0000000000000009

Copy DOI

Abstract

Chronic itch has been drawing much attention due to its clinical significance and the complexity of its mechanisms. To facilitate the development of anti-itch strategies, it is necessary to investigate the key players in itch sensation under chronic itch conditions. Several members of the Mrgpr family were identified as itch receptors that detect cutaneous pruritogens in primary sensory neurons. However, the role of Mrgprs in chronic itch conditions has not been well described. Scratching behaviors of WT and Mrgpr-clusterΔ-/- mice were examined in dry skin model and contact dermatitis model to examine the role of Mrgpr genes in mediating chronic itch sensation. Scratching behaviors of the mice were also examined in allergic itch model. Real-time PCR were performed to examine the expression level of MrgprA3 and MrgprC11 under naïve and dry skin conditions. The MrgprA3+ itch-sensing fibers were labeled by tdTomato fluorescence in Mrgpra3GFP-Cre; ROSA26tdTomato mice, and the morphology and density of those fibers in the epidermis were analyzed under dry skin condition. We showed that deleting a cluster of Mrgpr genes in mice reduced scratching behavior severely under two chronic itch conditions, namely dry skin and contact dermatitis, and the allergic itch condition. Moreover, the gene expressions of itch receptors MrgprA3 and MrgprC11 in dorsal root ganglia (DRG) were upregulated significantly under dry skin condition. Consistently, the percentage of MrgprA3+ itch-sensing neurons was increased as well. We also observed hyperinnervation of MrgprA3+ itch-sensing fibers in the epidermis of the skin under dry skin condition. We demonstrate that Mrgprs play important roles in mediating chronic itch and allergic itch. These findings enrich our knowledge of itch mechanism and may lead to the development of novel therapeutic approach to combat itch.

Highlights

Chronic itch has been drawing much attention due to its clinical significance and the complexity of its mechanisms
These results suggest that the deletion of Mrgpr genes did not affect the development of the dry skin model
Mrgpr-clusterΔ − / − mice exhibited significant decrease in scratching behavior compared with WT mice (Fig. 1C), suggesting that the activation of Mrgpr genes are required for dry skin itch

Summary

Introduction

Chronic itch accompanying cutaneous disease or systemic disorders is a serious condition[1,2,3]. MrgprA3, MrgprC11, and MrgprD have been identified as itch receptors that are expressed in small-diameter sensory neurons and directly detect pruritogens in the skin[9,11,12]. The expression of MrgprA3 defines a subset of nociceptors that mediate itch, but not pain[13]. These neurons express multiple itch receptors including MrgprA3, MrgprC11, and histamine receptor 1, and correspondingly respond to multiple pruritogens. We show that the scratching behaviors evoked under 2 chronic itch conditions, namely dry skin and contact dermatitis, were significantly suppressed in Mrgprs-deficient mice. Dry skin chronic itch condition increased the expression of itch receptors MrgprA3 and. We demonstrate that Mrgprs play a critical role in mediating chronic itch and allergic itch

Experimental procedures

Results

Discussion