Eosinophil - Nerve Interactions in Mouse Models of Dermatitis PROJECT SUMMARY: The recruitment, accumulation, and/or activities mediated by eosinophils (e.g., degranulation) have been hallmark features of cutaneous allergic diseases. These events also correlate with the dominant symptoms associated with these patients, including histopathological changes in the skin and behavioral responses such as itching that together often lead to a breakdown in cutaneous barrier functions. In addition, this link between eosinophils and allergic skin inflammation is noted in the available mouse models of dermatitis, suggesting an underlying role for these granulocytes. Unfortunately, despite the strong correlative relationship, the definition of eosinophil-mediated events leading to changes in the skin that promote inflammatory symptoms such as itch responses have remained out of reach. The goal of this collaborative proposal is to bridge this gap by exploiting our extensive experience examining eosinophil activities using allergen provocation models of lung disease. Indeed, our preliminary studies using skin inflammatory models have already greatly benefited from the availability of eosinophil-specific antibodies and our transgenic line of mice congenitall deficient of eosinophils. Our objective in this proposal is to exploit these resources as well as the development of a "next generation" gene knock-in mouse model (iPHIL) that permits the inducible and selective loss of eosinophils. This collaborative effort will focus our collective experiences studying eosinophils using mouse models of inflammatory diseases to define causative events contributing to the itching associated with allergic dermatitis. In particular, through the selective use of our novel in vivo mouse models and ex vivo eosinophil - nerve co-culture studies we will test the central hypothesis that interactions between skin infiltrating eosinophils and cutaneous sensory nerves increases nerve growth and branching, as well as increased expression of tachykinins. In turn, these remodeling events contribute to the itch response associated with dermatitis.
Eosinophils are rare white blood cells whose destructive capabilities were assumed to contribute to the structural changes of the skin linked with allergic inflammation. Nonetheless, a growing literature suggests that this perspective is too narrow and that eosinophils may even also interact with sensory nerves in the skin to elicit behaviors associated with allergic inflammation such as itching. Our creation and use of genetically engineered mice targeting eosinophils and their activities provide a mechanism with which to test this possibility. In particular, our creation of mice that are capable of becoming eosinophil-less on an "on demand" basis (iPHIL) provides a needed opportunity to define unambiguously the specific roles of eosinophil- nerve interactions during inflammatory responses that lead to itch responses.
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