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.

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