Atopic dermatitis (AD) is a chronic relapsing inflammatory condition of the skin that results from the interactions of the immune system with the structural cells in the skin. Cytokines produced by Th2 cells are critical promoters of atopic inflammation, and biological therapeutics that block the effects of IL-4, one of the Th2 cytokines, are efficacious in treatment of AD. Mechanistically, IL-4 potentiates inflammation by promoting chemokine production allowing increased recruitment of cells to the inflamed tissue, decreases expression of genes in keratinocytes that contribute to barrier function, and impairs innate pathogen defenses in the skin. We have added to our understanding of this process by demonstrating the ability of IL-4 to impair re- epithelialization of the skin after wounding. In a disease that is perpetuated by an itch-scratch-wound cycle, the inability to recover from wounds and restore barrier function is a critical component of chronic disease. Among the discoveries in our previous cycle of funding we demonstrated that keratinocytes exposed to IL-4 have impaired wound-healing responses both in vitro and in vivo using a model of atopic dermatitis. IL-4 stimulation repressed fibronectin expression in keratinocytes, and supplementing fibronectin either to cultures, or topically to wounded tissue in models of AD. Importantly, while wound healing has been studied extensively, how the atopic environment alters wound healing is completely unknown. In the next funding period we will define a re- epithelialization regulatory circuit that involves IL-4, ?? T cells, keratinocytes, and fibronectin. Experiments in the First Aim will define the IL-4-responsive cells that contribute to altered wound healing in models of AD. Based on preliminary data that there is a dramatic loss of ?? T cells in the skin of AD models, the Second Aim will determine how the ?? T cell contribution to wound healing is altered in an atopic environment. The final Third Aim will focus on testing the efficacy of topical fibronectin application in human skin transplant models. Together, the studies in these Aims will mechanistically define the interactions of immune and structural cells during a wound healing response in the context of an atopic environment, and will test potential new approaches to treating the pathology in AD.
Atopic dermatitis is an itchy, rash-inducing skin disease that affects around 10% of children and up to 3% of adults in the US. We have discovered that healing of skin wounds is altered in a model of atopic dermatitis. In this proposal, we investigate the mechanisms of this altered healing response by defining the role of specific soluble mediators and cells present in the skin.
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