Mechanisms of Itch in Poison Ivy-Induced Allergic Contact Dermatitis

毒藤引起的过敏性接触性皮炎的瘙痒机制

基本信息

批准号：
9164682
负责人：
SVEN-ERIC JORDT
金额：
$ 20.99万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9164682
关键词：
Acute Address Adrenal Cortex Hormones Adverse effects Affect Afferent Neurons Allergens Allergic Allergic Contact Dermatitis American Anaphylaxis Antibiotic Therapy Antihistamines Appearance Asthma Atopic Dermatitis Behavior Bulla CD4 Positive T Lymphocytes CXCL10 gene Caring Cells Child Clinical Complex Contact Dermatitis Cutaneous Cytokine Signaling Development Dose Dyes Edema Endothelin-1 Enzyme-Linked Immunosorbent Assay Epithelial Cells Esthesia Exanthema Exposure to Haptens Helper-Inducer T-Lymphocyte Hour Human IL1R1 gene Image Immune Immunohistochemistry Infectious Skin Diseases Inflammation Inflammatory Label Lead Learning Lesion Link Lymphoid Cell Mediating Modeling Mus Neurons Occupational Oxazolone Pathway interactions Peripheral Pilot Projects Plant Resins Plasma Population Production Proteins Pruritus Psoriasis Publishing Regimen Resistance Rhus radicans Role Serotonin Signal Pathway Skin Spinal Ganglia Swelling TSLP gene Testing Th2 Cells Transcript Vesicle Visit Work allergic response atmospheric carbon dioxide base chemokine climate change clinically relevant covalent bond cytokine in vivo injured innovation mouse model neutralizing antibody novel therapeutics patch clamp plant growth/development receptor response skin disorder symptom treatment transcriptome urushiol

项目摘要

Allergic contact dermatitis (ACD) is a common skin condition triggered by environmental or occupational allergens. In the US, the most common ACD is caused by contact with poison ivy with at least 10 million cases each year. Exposures to poison ivy have increased in recent years due to accelerated growth of the plants, increased production of allergens, and the spread of poison ivy to northern states, all of which are likely due to the increase in atmospheric carbon dioxide levels associated with climate change. The major clinical manifestations of poison ivy-induced ACD are skin rashes, swelling, and intense and persistent itch (pruritus), followed by the appearance of vesicles and bullae in severe cases. The severe itch sensation associated with poison ivy ACD triggers scratching behavior that is hard to control, especially in children, and further injures the skin. Antihistamines are generally ineffective for treating the pruritus associated with ACD. Scratching can also lead to skin infections that require antibiotic treatment. It is estimated that 50-75% of Americans are sensitized to urushiol, the primary allergen in poison ivy. However, surprisingly few published studies have explored in detail the pruritus mechanisms involved in poison ivy-induced ACD. Recent studies demonstrated that proinflammatory cytokines and chemokines, such as IL-31, TSLP and CXCL10 are endogenous pruritogens and activate corresponding receptors expressed in primary sensory neurons to produce pruritus. Blocking the signaling pathway of these endogenous pruritogens can effectively reduce pruritus behaviors in mouse itch models. IL-33 is an epithelial cell-derived proinflammatory cytokine, and signals via receptor ST2, which is highly expressed on Th2 cells and various types of innate immune cells. Recent evidence demonstrated the involvement of IL-33 in allergic skin diseases. In our pilot studies, mouse transcriptome microarray showed that IL-33 is significantly increased in the inflamed skin of mice with urushiol- induced ACD. We further found that ST2 receptor is expressed in a subset of dorsal root ganglion (DRG) neurons, including neurons that specifically innervate the skin. Therefore, our central hypothesis is that IL-33 acts via ST2 expressed in peripheral sensory neurons to produce pruritus, and that blocking IL-33/ST2 and other related endogenous pruritic pathways is effective against pruritus caused by urushiol-induced ACD. Successful completion of the work proposed here will 1) establish a link between IL-33 and poison ivy-induced ACD, 2) reveal a previously unrecognized interaction between IL-33 and primary sensory neurons, and 3) identify major pruritogens that cause the intense and persistent pruritus associated with poison ivy-induced ACD. Further, our pilot studies have shown that IL-33 receptor complex (ST2 and IL1R1) transcripts are expressed in human DRGs. Therefore, the proposed studies are highly significant because they are crucial steps toward the development of mechanism-based strategies to effectively treat the severe pruritus of poison ivy-induced ACD.

过敏性接触性皮炎 (ACD) 是一种由环境或职业引发的常见皮肤病过敏原。在美国，最常见的 ACD 是由接触毒藤引起的，至少有 1000 万例每年。近年来，由于植物生长加速，接触毒葛的情况有所增加，过敏原产量的增加以及毒藤向北部各州的传播，所有这些都可能是由于与气候变化相关的大气二氧化碳含量增加。主要临床毒藤引起的 ACD 的表现是皮疹、肿胀以及剧烈且持续的瘙痒（瘙痒），严重时会出现水疱和大疱。严重的瘙痒感与毒藤 ACD 会引发难以控制的抓挠行为，尤其是儿童，并进一步伤害皮肤。抗组胺药通常对治疗 ACD 相关的瘙痒无效。刮擦也可以导致需要抗生素治疗的皮肤感染。据估计 50-75% 的美国人对此敏感漆酚，毒葛中的主要过敏原。然而，令人惊讶的是，很少有已发表的研究对此进行了探讨详细介绍了毒藤引起的 ACD 所涉及的瘙痒机制。最近的研究表明，促炎细胞因子和趋化因子，如 IL-31、TSLP 和 CXCL10 是内源性瘙痒原，可激活初级感觉中表达的相应受体神经元产生瘙痒。阻断这些内源性瘙痒原的信号通路可以有效地减少小鼠瘙痒模型中的瘙痒行为。 IL-33是一种上皮细胞衍生的促炎细胞因子，并通过受体 ST2 发出信号，该受体在 Th2 细胞和各种类型的先天免疫细胞上高度表达。最近的证据表明 IL-33 与过敏性皮肤病有关。在我们的试点研究中，小鼠转录组微阵列显示，涂有漆酚的小鼠发炎皮肤中的 IL-33 显着增加。诱发ACD。我们进一步发现 ST2 受体在背根神经节 (DRG) 的一个子集中表达神经元，包括专门支配皮肤的神经元。因此，我们的中心假设是 IL-33 通过外周感觉神经元表达的 ST2 起作用，产生瘙痒，并阻断 IL-33/ST2 和其他相关的内源性瘙痒途径对漆酚诱导的ACD引起的瘙痒有效。成功完成此处提出的工作将 1) 建立 IL-33 和毒藤诱导之间的联系 ACD，2) 揭示了 IL-33 和初级感觉神经元之间以前未被识别的相互作用，以及 3) 识别导致与毒藤引起的强烈和持续性瘙痒相关的主要瘙痒原 ACD。此外，我们的初步研究表明 IL-33 受体复合物（ST2 和 IL1R1）转录物在人类 DRG 中表达。因此，拟议的研究非常重要，因为它们至关重要制定基于机制的策略以有效治疗严重中毒瘙痒的步骤常春藤诱发的ACD。