Tagoe, Hephzi;
Hassan, Sakinah;
Bliss, Emily;
Youssef, Gehad;
Heywood, Wendy;
Mills, Kevin;
Harper, John;
(2023)
Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype.
British Journal of Dermatology
10.1093/bjd/ljad095.
(In press).
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Abstract
BACKGROUND: Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales and often affects the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterised, however recent publications suggest that there are common mechanisms active in ichthyotic tissue, and in analogous models of ichthyosis. OBJECTIVE: To determine common mechanisms of hyperkeratosis that may be easily targeted with small molecule inhibitors. METHODS: We combined gene expression analysis of gene-specific shRNA knockdowns in rat epidermal keratinocytes of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Transglutaminase 1 (TGM1) and arachidonate 12-lipoxygenase, 12R type (ALOX12B), and proteomic analysis of skin scale from ARCI patients.as well as RNAseq data from rat epidermal keratinocytes treated with the Toll-like receptor-2 agonist PAM3CSK. RESULTS: we identified a common activation of the Toll-like receptor (TLR) 2 pathway. Exogenous TLR2 activation led to increased expression of important cornified envelope genes and in organotypic culture caused hyperkeratosis. Conversely, blockade of TLR2 signalling in ichthyosis patient keratinocytes and our shRNA models reduced the expression of keratin 1, a structural protein over-expressed in ichthyosis scale. A time-course of Tlr2 activation in rat epidermal keratinocytes revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread up-regulation of epidermal differentiation related proteins. Both NFκβ phosphorylation and Gata3 up-regulation was associated with this switch and Gata3 overexpression was sufficient to increase Keratin 1 expression. CONCLUSION: Taken together, these data define a dual role for Toll-like receptor 2 activation during epidermal barrier repair, that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.
Type: | Article |
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Title: | Chronic activation of Toll-like receptor 2 induces an ichthyotic skin phenotype |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1093/bjd/ljad095 |
Publisher version: | https://doi.org/10.1093/bjd/ljad095 |
Language: | English |
Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
Keywords: | Science & Technology, Life Sciences & Biomedicine, Dermatology, PREVENTS HYPERKERATOSIS, GENE-EXPRESSION, IKK-ALPHA, BARRIER, DIFFERENTIATION, TLR2, MUTATIONS, DELETION, NEWBORN, ALOX12B |
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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10171901 |
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