Mechanoregulation of the epidermal immune response: the role of desmoglein 1

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Project Summary The epidermis of the skin provides an essential barrier between the organism and the environment. Disruption of the epidermal barrier is associated with chronic inflammatory diseases such as psoriasis and atopic dermatitis. Affected areas in patients with these diseases are frequently distributed in regions that experience higher amounts of mechanical stress, such as the extensor areas in psoriasis and flexor regions in atopic dermatitis. The underlying basis of sensitivity to mechanical stress in these diseases is unknown. Desmosomes are intercellular junctions that are critical for both formation of the barrier and for providing mechanical strength to the epidermis and are abundant in tissues that experience large amounts of mechanical stress. The desmosomal cadherin Desmoglein 1 (Dsg1) is only expressed in stratified epithelium such as the epidermis and is critical for proper epidermal development and function. Mutations in Dsg1 causes severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome, a chronic inflammatory disease associated with recurrent skin infections, abnormal epidermal differentiation and loss of adhesion between keratinocytes. Barrier defects in these patients may explain some of the inflammation present in the skin; however, isolated keratinocytes continue to express increased proinflammatory cytokine levels in cell culture. Knockdown of Dsg1 in normal primary keratinocytes also causes an increase in proinflammatory cytokine expression. These data raise the possibility that Dsg1 contributes to inflammatory responses. Other evidence indicates that Dsg1 may act as a stress sensor. Dsg1 is downregulated by several types of environmental stress, including exposure to UV. Preliminary data show that Dsg1 is downregulated in differentiated keratinocytes exposed to mechanical stress. Mechanical stress also increases expression of proinflammatory cytokines in keratinocytes, many of which overlap with those increased in keratinocytes after knockdown of Dsg1. This proposal will test the hypothesis that Dsg1 is a mechanical stress sensor and regulates epidermal inflammatory responses. Aim 1 seeks to identify the mechanism by which Dsg1 regulates cytokine expression in keratinocytes. This aim will also test the extent to which the downregulation of Dsg1 in response to mechanical stress regulates increased cytokine expression. Aim 2 will determine the molecular mechanism by which mechanical stress downregulates Dsg1 levels in keratinocytes. Preliminary data indicate that Dsg1 is also downregulated in response to oxidative stress, and the extent to which increased oxidative stress induced by mechanical insult downregulates Dsg1 will be tested. Increasing our knowledge of mechanisms by which mechanical stress drives inflammatory responses will improve our understanding of diseases such as psoriasis and atopic dermatitis, and potentially identify new targets for developing more effective therapies.