@phdthesis{Phan2021kerat-54803,
  year={2021},
  title={The role of keratinocyte glucocorticoid synthesis in skin homeostasis and inflammation},
  author={Phan, Truong San},
  address={Konstanz},
  school={Universität Konstanz}
}

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    <dc:language>eng</dc:language>
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    <dcterms:abstract xml:lang="eng">Glucocorticoids (GC) represent one of the most extensively investigated and applied drugs that is widely used against inflammatory diseases and cancer. Despite the research in immunosuppressive mechanisms and the pharmaceutical invention of synthetic GCs, the exact mechanisms of endogenous GC-mediated actions are still poorly understood. Although endogenous GCs are mainly produced in the adrenal cortex, emerging research revealed the existence of extra-adrenal GCs at epithelial barrier tissues of the body. The first part of the thesis reviews the current knowledge of extra-adrenal GC synthesis and discusses potential linkages between barrier tissue GC synthesis and inflammatory diseases. Interestingly, disrupted epithelial barriers and associated aggravated immune responses are the basis of several inflammatory disorders in skin and other organs. The GC synthesis pathway in human skin was recently described and involves cytochrome P450 enzymes such as the 11β-hydroxylase (Cyp11b1) catalyzing the final step in the synthesis. However, the physiological relevance and function of cutaneous GCs remain unexplored. Therefore, the main part of the thesis aims to unravel the role of keratinocyte GC synthesis in the regulation of skin homeostasis and inflammation. This was experimentally approached by in vivo abrogation of skin GC synthesis using a mouse model with inducible Cyp11b1 knockout (KO) in keratinocytes. The characterization of the in vivo steroidogenic capacity of mouse skin demonstrated adrenal-independent de novo synthesis of GCs and its responsiveness toward neuropeptides and inflammatory signaling compared to KO skin. In addition, we investigated whether deficient GC synthesis in the skin can contribute to the pathogenesis of inflammatory skin disease and how it affects skin inflammation in corresponding pre-clinical mouse models. While preceding changes in skin-derived dendritic cell emigration indicated skin immune priming in KO mice, contact hypersensitivity induction further resulted in increased skin inflammation. Furthermore, an atopic dermatitis (AD) model was applied to investigate the impact of abrogated skin GC synthesis on type 2 skin immune responses. While AD skin inflammation was unchanged in KO mice, pruritus along with IL-4 skin levels were shown to be reduced. In contrast, induced psoriasiform skin inflammation was exacerbated in KO mice demonstrating fast, increased skin immune cell infiltration and tissue damage associated with elevated IL-17A levels that are mostly produced by CD8+ γδT cells. Together these results not only demonstrate inflammation-dependent and context-enhanced local GC synthesis, but they also underscore the differential actions of endogenous skin GCs in controlling various inflammatory skin diseases as observed by the biased immune responses in the absence of skin GCs. Additional experiments further showed that long-term GC deficiency resulted in the spontaneous development of skin inflammation with type 1/3 immune responses indicating a crucial role of skin GCs in maintaining homeostatic processes in the skin. Altogether, the results experimentally demonstrate the endogenous potential of skin GCs in controlling skin homeostasis in health and disease emphasizing a novel regulatory mechanism of the cutaneous neuroendocrine system. The presented thesis thus provides a novel perspective of skin GCs to control systemic inflammation across the integumentary system such as atopic diseases that are associated with skin sensitization. Hence, keratinocyte GCs not only control local homeostasis but possibly hold potential in preventing the pathogenesis of systemic diseases that originate in the skin.</dcterms:abstract>
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