Abstract

While imiquimod (IMQ) has been widely used in dermatology, its side effect manifested as dermatitis couldn’t be ignored. However, the underlying mechanism has not been fully understood. Considering the clinical features of IMQ-related dermatitis similar to pseudo-allergic reaction and the presence of large numbers of mast cell in tissues treated with IMQ, the possibility that IMQ-related dermatitis mediated by mast cell-specific Mas-related G protein-coupled receptor X2 (MRGPRX2) should be addressed. To investigate the role of MRGPRX2 in vivo, MrgprB2, the mice homology of human MRGPRX2, was detected in IMQ-induced dermatitis mouse model. Histopathological changes including mast cell degranulation and footpad swelling were assayed in wild-type and MrgprB2^−/− mice. The results showed that IMQ application induced dermatitis and footpad swelling with inflammatory cells infiltration plus mast cell activation in the skin of wild-type mice but reduced significantly in MrgprB2^−/− mice. Further, compared to wild-type mice, serum histamine and inflammatory cytokine levels were compromised in MrgprB2^−/− mice treated with IMQ, while the serum IgE level didn’t change significantly. In vitro studies, levels of mediators released from murine peritoneal mast cells (MPMCs) after IMQ treatment were increased in a dose-dependent manner, which was much mild in MPMCs from MrgprB2^−/− mice. Intracellular Ca²⁺ concentration was increased in a dose-dependent manner after IMQ treatment both in MrgprB2-HEK293 and MRGPRX2-HEK293 cells. Moreover, β-hexosaminidase released after IMQ treatment was blocked by siRNA directed at the MRGPRX2 receptor in LAD2 cells. In summary, MrgprB2 /MRGPRX2 mediate mast cell activation and participate in IMQ-related dermatitis.

PAR2 mediates itch via TRPV3 signaling in keratinocytes

Jiahui Zhao, Admire Munanairi, Xian-Yu Liu, Jie Zhang, Linghan Hu, Meiqin Hu, Dingfang Bu, Lingling Liu, Zhiqiang Xie, Brian S. Kim, Yong Yang, Zhou-Feng Chen

The Journal of Investigative Dermatology

20 August 2019
10 December 2019 12 January 2020

Please cite this article as: Zhao J, Munanairi A, Liu X-Y, Zhang J, Hu L, Hu M, Bu D, Liu L, Xie Z,
Kim BS, Yang Y, Chen Z-F, PAR2 mediates itch via TRPV3 signaling in keratinocytes, The Journal of Investigative Dermatology (2020), doi: https://doi.org/10.1016/j.jid.2020.01.012.

Abstract

Animal studies have suggested that transient receptor potential (TRP) ion channels and G protein-coupled receptors (GPCRs) play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis (AD), whereas their inhibition attenuated scratching and inflammatory responses in mouse AD models. Taken together, these results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in AD.

Key Words

TRPV3PAR2itchkeratinocytescalciumatopic dermatitis

Abbreviations

ADatopic dermatitisBAM 8-22bovine adrenal medulla peptide 8-22DRGdorsal root gangliaGPCRG protein coupled receptorMrgprMas-related G-protein coupled receptorPAR2protease-activated receptor 2TRPV3transient receptor potential cation channel V3TSLPthymic stromal lymphopoietin