Disentangling the Epidermal Immune Crosstalk in Inflammatory Skin Disease

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Project Summary/ Abstract Inflammatory skin diseases are often multifactorial, with influences from genetics and environmental factors that cause immune dysregulation and impair skin barrier integrity. The epidermis is the outermost layer of the skin and is fundamental to maintaining skin barrier integrity. Also, epidermal skin cells play a primary role in the recruitment and regulation of immune cells upon disruption of homeostasis. The mechanisms that govern the crosstalk between the epidermis and the immune system have yet to be fully elucidated. Current strategies in treating inflammatory skin disease include the administration of corticosteroids and retinoids, which may have unwanted side effects with prolonged use. Therefore, there is a need for a better mechanistic understanding of the crosstalk between the epidermis and the immune system to develop more targeted approaches to treat inflammatory skin disease. Recent reports have implicated SNPs in genes that may play a role in inflammatory skin diseases. One such gene is Ovol1. Ovol1 is a transcriptional repressor of immune cell recruitment and is necessary for maintaining skin homeostasis and regulating proper embryonic epidermis development. Ablation of Ovol1 in psoriasis-like and atopic dermatitis animal models exacerbates disease with an increase of infiltrating neutrophils. Ablation of neutrophils improves disease outcomes. Neutrophils are the principal innate immune responders forming the first line of defense against pathogenic invaders or sterile damages. Neutrophils have an arsenal of effector functions, including the engulfment of pathogens, release of proteases, extracellular trap formation, and release of reactive oxygen species. Appropriately, neutrophils have a destructive potential that requires stringent regulation of recruitment to avoid excess collateral damage to the host. Our preliminary data show that in the absence of epidermal Ovol1, the recruitment of neutrophils to the injured skin increases in minutes. This observation suggests that Ovol1 has a gatekeeping function and prevents the excessive production of neutrophil chemoattractants after skin injury. My central hypothesis is that Ovol1 regulates the production of leukotrienes as well as the expression of chemokines before or minutes after wounding. The absence of epidermal Ovol1 primes the skin for neutrophil infiltration, in turn exacerbating inflammatory skin disease. In this proposal, I will address two aims to support my hypothesis: 1) Evaluate the role of leukotrienes in the excessive recruitment of neutrophils in the absence of epidermal Ovol1, 2) Identify and block chemokines expressed early after skin injury when Ovol1 is absent. The proposed research will untangle the early crosstalk between the epidermis and the innate immune system, potentially revealing better pharmacological targets to alleviate inflammatory skin disease.