State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, China.
J Allergy Clin Immunol. 2021 Jun;147(6):2236-2248.e16. doi: 10.1016/j.jaci.2020.12.626. Epub 2020 Dec 22.
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.
This study sought to discover potent drugs and targets for the specific prevention and treatment of tick bite-induced pruritus and arthropod-related itch.
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.
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.
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.
蜱叮咬严重威胁人类健康，因为它们可以传播许多致命病原体，包括病毒、细菌、原生动物和寄生虫。瘙痒是蜱叮咬的主要症状，但它的分子和神经基础仍然难以捉摸。
本研究旨在发现针对蜱叮咬引起的瘙痒和节肢动物相关瘙痒的特定预防和治疗的有效药物和靶点。
我们使用活细胞钙成像、膜片钳记录和基因缺失，并评估小鼠行为，以研究蜱叮咬引起瘙痒的分子和神经基础。
我们发现 2 种蜱唾液肽，IP 防御素 1（IPDef1）和 IR 防御素 2（IRDef2），在小鼠中引起瘙痒。进一步发现 IPDef1 比 IRDef2 具有更强的致痒潜力，并且以组胺非依赖性方式引起瘙痒。IPDef1 通过激活背根神经节神经元上的小鼠 MrgprC11 和人 MRGPRX1 来诱发瘙痒。IPDef1 激活的 MrgprC11/X1 信号使下游离子通道 TRPV1 在背根神经节神经元上敏化。此外，IPDef1 还激活了小鼠 MrgprB2 和其在肥大细胞上选择性表达的同源物人 MRGPRX2，诱导炎症细胞因子的释放，并在小鼠中引发急性炎症，尽管肥大细胞激活不参与氧化 IPDef1 诱导的瘙痒。
本研究确定蜱唾液肽是一种新的致痒原类，通过 MrgprC11/X1-TRPV1 信号在瘙痒感受器中引发瘙痒。我们的工作将为预防和治疗蜱和其他节肢动物叮咬或刺伤引起的瘙痒提供潜在的药物靶点。
