Xueke Li1, Haifeng Yang1, Yuewen Han1, Shijin Yin2, Bingzheng Shen1, Yingliang Wu1, Wenxin Li1, Zhijian Cao3. 1. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China. 2. School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China. 3. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China; Bio-drug Research Center, Wuhan University, Wuhan, China; Hubei Province Engineering and Technology Research, Center for Fluorinated Pharmaceuticals, Wuhan University, Wuhan, China. Electronic address: zjcao@whu.edu.cn.
Abstract
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 a histamine-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.
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 a histamine-independent manner. IPDef1 evoked itch by activating mouseMrgprC11 and humanMRGPRX1 on dorsal root ganglion neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on dorsal root ganglion neurons. Moreover, IPDef1 also activated mouseMrgprB2 and its ortholog humanMRGPRX2 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.