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

• 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
• 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

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.

变应性接触性皮炎（ACD）是一种常见的皮肤病，由环境或职业 过敏原在美国，最常见的ACD是由接触毒葛引起的，至少有1000万例 每年.近年来，由于毒藤的加速生长， 过敏原的产生增加，以及毒葛向北方各州的蔓延，所有这些都可能是由于 与气候变化有关的大气二氧化碳水平的增加。主要临床 毒藤诱导的ACD的表现是皮疹、肿胀和强烈且持续的瘙痒（瘙痒症）， 严重者出现水疱和大疱。严重的瘙痒感与 毒葛ACD会引发难以控制的抓挠行为，尤其是在儿童中，并进一步伤害 皮肤抗组胺药通常对治疗ACD相关瘙痒症无效。此外， 导致需要抗生素治疗皮肤感染。据估计，50-75%的美国人是敏感的， 漆酚毒葛的主要过敏原然而，令人惊讶的是， 详细描述了毒藤诱导的ACD中涉及的瘙痒机制。 最近的研究表明，促炎细胞因子和趋化因子，如IL-31，TSLP和 CXCL 10是内源性促炎原，并激活初级感觉神经元中表达的相应受体。 神经元产生瘙痒。阻断这些内源性促炎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是上皮细胞衍生的促炎细胞因子， 并通过受体ST 2发出信号，该受体ST 2在Th 2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-33参与过敏性皮肤病。在我们的初步研究中，老鼠 转录组微阵列显示，IL-33在漆酚小鼠的发炎皮肤中显著增加， 诱发ACD。我们进一步发现，ST 2受体在背根神经节（DRG）的一个亚群中表达。 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中表达的ST 2起作用以产生瘙痒，并且阻断IL-33/ST 2和 其它相关的内源性瘙痒途径对漆酚诱导的ACD引起的瘙痒有效。 成功完成这里提出的工作将1）建立IL-33和毒藤诱导的 ACD，2）揭示了IL-33和初级感觉神经元之间先前未被认识的相互作用，以及3） 确定引起毒藤诱导的强烈和持续瘙痒的主要致敏原 ACD。此外，我们的初步研究表明，IL-33受体复合物（ST 2和IL 1 R1）转录物是 在人DRG中表达。因此，拟议的研究非常重要，因为它们至关重要 逐步发展基于机制的策略，以有效治疗中毒性严重瘙痒症 常春藤诱导的ACD。