Atopic dermatitis occurs as a result of inappropriate immune responses to common elements in the environment. The T-helper type II (Th2) lymphocyte is a critical contributor to the pathologic inflammatory responses observed in these patients. For example, atopic dermatitis is characterized by increased levels of the Th2 cytokines, IL-4 and IL-13, in the skin. When keratinocytes are cultured with either IL-4 or IL-13 they respond by producing a variety of pro-inflammatory mediators and they lose expression of filaggrin as well as loricrin and involucrin, which are important proteins that maintain skin barrier function. However, there have been no studies performed to test the in vivo relevance of IL-4 and IL-13 acting directly on keratinocytes in the pathologies associated with atopic dermatitis. IL-4 and IL-13 signal by ligation of a common receptor, IL- 4Ra. Our hypothesis is that IL-4Ra signaling specifically in keratinocytes contributes to inflammation and failure of skin barrier function in a murine model of atopic dermatitis. The main objective is to determine the in vivo requirement for keratinocyte-specific expression of IL-4Ra in the development of skin pathologies associated with experimental atopic dermatitis. We will accomplish this objective by completing two specific aims.
Specific Aim 1 : To generate a mutant mouse strain that is deficient in IL-4Ra exclusively in keratinocytes. We will breed commercially available K14-Cre mice with our IL-4Ra flox/flox mice. The K14- Cre mice have expression of Cre-recombinase (Cre) only in keratinocytes. IL-4Ra flox/flox mice have Crebinding loxP sequences that flank exons 7 -9 of the IL-4Ra gene. When the two strains of mice are bred, the double mutant mice have expression of Cre only in keratinocytes causing keratinocyte-specific deletion of the IL-4Ra gene. Otherwise, these mice have normal IL-4 and IL-13 signaling in every other cell type.
Specific Aim 2 : To determine the in vivo requirement for keratinocyte-specific expression of IL-4Rct in the development of skin pathology associated with experimental atopic dermatitis. We anticipate that mice with keratinocyte-specific IL-4Ra deletion will be protected from inflammation and failure of skin barrier function as elicited in a well-characterized mouse model of atopic dermatitis.

Public Health Relevance

If we find evidence supporting the in vivo importance of IL-4/13-keratinocyte interaction in atopic dermatitis, this will provide rationale for a clinical study to test if local applicaton of already developed IL-4Ra blocking reagents improved the condition of patients with atopic dermatitis and possibly other skin diseases. For example, IL-4 and IL-13 are also implicated in the pathology associated with contact dermatitis and urticaria.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Center Core Grants (P30)
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Special Emphasis Panel (ZAR1)
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Northwestern University at Chicago
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