Mechanisms of Itch in Poison Ivy-Induced Allergic Contact Dermatitis

过敏性接触性皮炎(ACD)是一种常见的皮肤疾病，由环境或职业引起 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，由于毒藤的生长速度加快，毒藤的暴露有所增加， 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水平的增加。主要的临床 毒藤引起的ACD的表现是皮疹、肿胀和强烈而持久的瘙痒(瘙痒)， 严重者可出现水泡和水泡。严重的瘙痒感伴随着 有毒常春藤ACD会引发难以控制的抓挠行为，特别是在儿童中，并进一步损害 皮肤。抗组胺药对ACD相关的瘙痒通常无效。抓挠也可能 导致皮肤感染，需要抗生素治疗。据估计，50%-75%的美国人有敏感症 对漆酚，有毒常春藤的主要过敏原。然而，令人惊讶的是，很少有已发表的研究在 详细介绍毒藤诱导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，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 减少小鼠瘙痒模型的瘙痒行为。IL-33是一种上皮细胞衍生的促炎细胞因子， 和信号通过受体ST2，它在Th2细胞和各种类型的天然免疫细胞上高表达。 最近的证据表明，IL-33参与了过敏性皮肤病的发病。在我们的先导研究中，老鼠 转录组芯片结果显示，漆酚致炎小鼠皮肤中IL-33的表达显著增加。 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 通过在外周感觉神经元中表达的ST2来产生瘙痒，并阻断IL-33/ST2和 其他相关的内源性瘙痒通路对漆酚诱导的ACD引起的瘙痒有效。 这里提出的工作的成功完成将1)在IL-33和毒藤诱导之间建立联系 ACD，2)揭示了以前未知的IL-33和初级感觉神经元之间的相互作用，以及3) 确定引起与毒藤诱导的强烈和持续瘙痒相关的主要瘙痒原 ACD。此外，我们的初步研究表明，IL-33受体复合体(ST2和IL1R1)转录本是 在人类DRG中表达。因此，拟议的研究具有重要意义，因为它们至关重要。 开发有效治疗毒物严重瘙痒的基于机制的策略的步骤 常春藤诱导的ACD。

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.