UC Irvine

The skin barrier has plethora of important functions including protection from and triggering the inflammatory response to mechanical, thermal and physical injury and provides insulation against moisture loss. Skin barrier is formed by the continuous proliferation and maturation of keratinocytes. The focus of this dissertation is to understand epithelial barrier regulation and immune crosstalk, and how dysfunctional barrier can cause systemic physiological response.Chapter 3 expands upon a previous study and aims to understand the triggers and dynamics of neutrophil recruitment into skin during TLR7-induced skin inflammation. Previous work showed a protective role of Ovol1 in mediating the epidermal keratinocyte differentiation response and inflammatory response to psoriatic-like inflammation. However, the molecular mechanism by which Ovol1 mediates these responses, including the infiltration and migration of neutrophils was unknown. During development Ovol1 facilitates differentiation of keratinocytes through promoting growth arrest of progenitor cells; however, the skin-specific function of Ovol1, especially in adulthood and during inflammation was unknown. This work showed a critical function of Ovol1 in regulating barrier and unraveled a novel function for Ovol1 in both directly and indirectly mediating inflammation. Using genetic mouse models and immunological assays, we show that loss of Ovol1 resulted in exacerbated barrier defects following imiquimod (IMQ) treatment of the back skin, followed by elevated neutrophil recruitment to the skin. We find that Ovol1 balances the extent of inflammation by repressing neutrophil recruitment through mitigating barrier-induced Il1a release, repression of Cxcl1 transcription. Interestingly, we also found Ovol1 promotes epidermal hyperplasia by repressing of Il33 suggesting Ovol1 is important for balancing epidermal maintenance with inflammation. Chapter 4 utilizes multidisciplinary biological assays and high throughput sequencing technologies to understand Ovol1 and Ovol2 function in barrier maintenance during adult homeostasis and how barrier defects can affect total body physiology. The current work expands a previous study showing that Ovol1 and Ovol2 are important for the development of barrier during embryogenesis through modulating epithelial differentiation and adhesion. In the current work I take a wholistic and unbiased approach to focus on the biological and molecular function of Ovol1 and Ovol2 in adult homeostasis and established an epithelial-specific genetic knock out mouse model (K14-CreER;Ovol1f/-;Ovol2f/-) as a system to explore epidermal cross-talks and the contribution of barrier to physiological homeostasis. I show that inducible deletion of Ovol1 and Ovol2 in adulthood leads to spontaneous barrier defects, followed by activation of epidermal Langerhans cells, aberrant T cell response, reduced body weight, and altered metabolism. I find that Ovol1 and Ovol2 are important for regulating many genes associated with cytoskeletal structure and adhesion and loss of both results in increased epithelial to mesenchymal plasticity and aged molecular signature in epidermis. Moreover, I show that that Ovol1 and Ovol2 knock out mice have increased immune cells, namely T cells in the skin-draining lymph nodes followed by increased energy expenditure and restricted fat accumulation over time. Importantly, inhibition of inflammation through continuous dexamethasone treatments partially rescues epidermal Langerhans cell activation and body weight phenotype suggesting that inflammation is partially instigating changes to whole body metabolism. This study suggests the importance of barrier in maintaining total body homeostasis through suppressing aberrant immune activation. Overall, this thesis work combines multidisciplinary methods to broadly understand epidermal-immune cross talks and the role barrier plays in inflammation and in protecting total-body physiology, but also focuses on direct transcriptional regulation of gens involved in barrier that can trigger systemic responses.