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; 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.

过敏性接触性皮炎（ACD）是由环境或职业触发的常见皮肤状况 过敏原。在美国，最常见的ACD是由至少1000万例毒药的接触引起的 每年。由于植物的加速生长，近年来对毒藤的暴露量增加了， 过敏原的产量增加，毒种常春藤传播到北部各州，所有这些都可能是由于 与气候变化相关的大气二氧化碳水平的增加。主要的临床 常春藤引起的ACD的表现是皮疹，肿胀，强烈，持续的瘙痒（瘙痒）， 然后在严重的情况下出现囊泡和大麻。与 毒Ivy ACD触发难以控制的刮擦行为，尤其是在儿童中，并进一步伤害 皮肤。抗组胺药通常无效地治疗与ACD相关的瘙痒。刮擦也可以 导致需要抗生素治疗的皮肤感染。据估计，有50-75％的美国人敏感 对于毒药，毒药中的主要过敏原。但是，令人惊讶的是，很少有发表研究在 详细介绍毒性常春藤诱导的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，例如IL-31，TSLP和 CXCL10是内源性耐药的，并激活在一级感觉中表达的相应受体 神经元产生瘙痒。阻止这些内源性耐药的信号传导途径可以有效地 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， 以及通过受体ST2的信号，该信号在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-33参与过敏性皮肤疾病。在我们的试点研究中，鼠标 转录组微阵列表明，用Urushiol-的小鼠发炎的皮肤IL-33显着增加 诱导的ACD。我们进一步发现，ST2受体在背根神经节（DRG）的一部分中表达 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 通过在外围感觉神经元中表达的ST2作用以产生瘙痒，并阻止IL-33/ST2和 其他相关的内源性核途径有效抵抗由Urushiol诱导的ACD引起的瘙痒。 成功完成此处提出的工作的完成1）建立IL-33与毒药引起的联系 ACD，2）揭示了IL-33与原发性神经元之间以前未被认可的相互作用，以及3） 识别引起与毒药诱导的强烈和持久性瘙痒的主要野生型元素 ACD。此外，我们的初步研究表明，IL-33受体复合物（ST2和IL1R1）的转录本是 用人类DRG表示。因此，拟议的研究非常重要，因为它们至关重要 迈向开发基于机制的策略以有效治疗毒药严重瘙痒的步骤 常春藤诱导的ACD。