Tick peptides evoke itch by activating MrgprC77/MRGPRX7 to sensitize TRPV7 in pruriceptors

Background: Tick bites severely threaten human health because they allow the transmission of many deadly pathogens, including viruses, bacteria, protozoa, and helminths. Pruritus is a leading symptom of tick bites, but its molecular and neural bases remain elusive. Objectives: This study sought to discover potent drugs and targets for the specific prevention and treatment of tick bite-induced pruritus and arthropod-related itch. Methods: We used live-cell calcium imaging, patch-clamp recordings, and genetic ablation and evaluated mouse behavior to investigate the molecular and neural bases of tick bite-induced pruritus. Results: We found that 2 tick salivary peptides, IP defensin 1 (IPDef1) and IR defensin 2 (IRDef2), induced itch in mice. IPDef1 was further revealed to have a stronger pruritogenic potential than IRDef2 and to induce pruritus in ahistamine-independent manner. IPDef1 evoked itch by activating mouse MrgprC11 and human MRGPRX1 on dorsal root ganglion neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on dorsal root ganglion neurons. Moreover, IPDef1 also activated mouse MrgprB2 and its ortholog human MRGPRX2 selectively expressed on mast cells, inducing the release of inflammatory cytokines and driving acute inflammation in mice, although mast cell activation did not contribute to oxidated IPDef1-induced itch. Conclusions: Our study identifies tick salivary peptides as a new class of pruritogens that initiate itch through MrgprC11/ X1-TRPV1 signaling in pruritoceptors. Our work will provide potential drug targets for the prevention and treatment of pruritus induced by the bites or stings of tick and maybe other arthropods. (J Allergy Clin Immunol 2021;147:2236-48.)

Automated summary

This study identified tick salivary peptides as pruritogens that initiate itch through MrgprC11/X1-TRPV1 signaling in pruritoceptors. The findings provide potential drug targets for the prevention and treatment of pruritus induced by tick bites or other arthropods. IPDef1 was found to have a stronger pruritogenic potential than IRDef2 and induced itch in a histamine-independent manner.