Huang, Xin;
(2024)
The influence of increased Kallikrein 5 in keratinocytes in inflammatory immuno-response.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Atopic dermatitis (AD) is a multi-factorial inflammatory skin disease caused by genetic and environmental factors. AD has a disrupted skin barrier, resulting in external allergens easily penetrating through the barrier and leading to Th2 immune response. Abnormalities of proteins in the skin can cause dysfunctional skin barrier and enhanced serine proteases Kallikrein 5 (KLK5) is one of them. Studies showed enhanced KLK5 could impair the skin barrier integrity by over- degrading the adhesion protein and upregulate cytokines. I proposed to investigate the relationship between enhanced KLK5 in keratinocytes and immuno-response in the skin. The transcriptome changes were first examined in keratinocytes overexpressing KLK5. The results showed no differentiated genes directly related to immuno- response. However, genes involved in the TGF-β signaling were down-regulated. Secondly, the culture media from keratinocytes with KLK5 overexpression were checked. Increased IL-2 and IL-6 and decreased TSLP were found. To confirm if these cytokines play a paracrine effect on Th2 immuno-response in the skin, human naïve CD4+ T cells were treated with this conditional medium. Increase of Th2 differentiation was found in treated cells from three out of six donors, suggesting there might be a link between enhanced KLK5 in keratinocytes and Th2 differentiation with individual variations. Finally, based on the evidence that KLK5 was enhanced in AD-lesional skin but not in non-lesional skin, a cell model with inducible KLK5-GFP overexpression was developed using the lentiviral vector containing TRE3GS promoter controlled by doxycycline. The KLK5-GFP over-expression was observed following doxycycline induction, and it could be reversed once Doxycycline treatment was withdrawal. In conclusion, enhanced KLK5 in keratinocytes down-regulated TGF-b signaling and increased cytokine secretions in keratinocytes, which could influence Th2 differentiation in certain donors. An inducible KLK5 overexpression keratinocyte model was also developed, providing a new tool for investigating KLK5 activity and skin barrier function.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The influence of increased Kallikrein 5 in keratinocytes in inflammatory immuno-response |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10185714 |
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