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.
Poison ivy-induced allergic contact dermatitis (ACD) is the most common ACD in the US and affects over 10 millions of Americans every year. It is characterized by skin rashes, edema, blister, lesion, as well as severe itch (pruritus) sensations that are hard to control and resistant to conventional antihistamine treatment. This proposal aims to address how to treat the severe pruritus in posion ivy-induced ACD by identifying and targeting specific endogenous pruritogens and signaling pathways. These efforts can help to discover novel therapies for treating the severe pruritus associated with poison ivy-induced ACD.
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