The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy and Clinical Immunology, Center for Immunology, Inflammation, and Immune-mediated disease, Guangzhou Medical University, Guangzhou, China.
Center for the Study of Itch, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA; Barnes-Jewish Hospital, St. Louis, Missouri, USA.
J Invest Dermatol. 2020 Sep;140(9):1856-1866.e7. doi: 10.1016/j.jid.2020.01.016. Epub 2020 Feb 5.
Recurrent and intractable chronic itch is a worldwide problem, but mechanisms, especially the neural mechanisms, underlying chronic itch still remain unclear. In this study, we investigated the peripheral and spinal mechanisms responsible for prolonged itch in a mouse model of allergic contact dermatitis induced by squaric acid dibutylester. We found that repeated exposure of mice to squaric acid dibutylester evoked persistent spontaneous scratching and significantly aberrant cutaneous and systemic immune responses lasting for weeks. Squaric acid dibutylester-induced itch requires both nonhistaminergic and histaminergic pathways, which are likely relayed by GRPR and NPRA in the spinal cord, respectively. Employing genetic, pharmacologic, RNAscope assay, and cell-specific ablation methods, we dissected a neural circuit for prolonged itch formed as Grpr neurons act downstream of Npr1 neurons in the spinal cord. Taken together, our data suggested that targeting GRPR and NPRA may provide effective treatments for allergic contact dermatitis-associated chronic pruritus.
复发性和难治性慢性瘙痒是一个全球性问题，但慢性瘙痒的机制，特别是神经机制，仍然不清楚。在这项研究中，我们研究了由丁二酸二丁酯诱导的过敏性接触性皮炎的小鼠模型中导致长期瘙痒的外周和脊髓机制。我们发现，重复暴露于丁二酸二丁酯的小鼠会引起持续的自发性搔抓，并持续数周出现明显异常的皮肤和全身免疫反应。丁二酸二丁酯诱导的瘙痒需要非组胺能和组胺能途径，这两条途径可能分别由脊髓中的 GRPR 和 NPRA 传递。通过使用遗传、药理学、RNAscope 检测和细胞特异性消融方法，我们在脊髓中发现了一个由 Grpr 神经元作用于 Npr1 神经元下游而形成的长期瘙痒的神经回路。总之，我们的数据表明，靶向 GRPR 和 NPRA 可能为治疗过敏性接触性皮炎相关的慢性瘙痒提供有效的治疗方法。
