{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:32:09Z","timestamp":1789731129954,"version":"4.0.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T00:00:00Z","timestamp":1679875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000296","name":"British Skin Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000296","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002886","name":"Foundation for Ichthyosis and Related Skin Types","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002886","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Great Ormond Street Children\u2019s Charity"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Ichthyosis defines a group of chronic conditions that manifest phenotypically as a thick layer of scales, often affecting the entire skin. While the gene mutations that lead to ichthyosis are well documented, the actual signalling mechanisms that lead to scaling are poorly characterized; however, recent publications suggest that common mechanisms are active in ichthyotic tissue and in analogous models of ichthyosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine common mechanisms of hyperkeratosis that may be easily targeted with small-molecule inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We combined gene expression analysis of gene-specific short hairpin RNA (shRNA) knockdowns in rat epidermal keratinocytes (REKs) of two genes mutated in autosomal recessive congenital ichthyosis (ARCI), Tgm1 and Alox12b, and proteomic analysis of skin scale from patients with ARCI, as well as RNA sequencing data from rat epidermal keratinocytes treated with the Toll-like receptor 2 (TLR2) agonist Pam3CSK4.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified common activation of the TLR2 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 keratinocytes from patients with ichthyosis and our shRNA models reduced the expression of keratin 1, a structural protein overexpressed in ichthyosis scale. A time course of TLR2 activation in REKs revealed that although there was rapid initial activation of innate immune pathways, this was rapidly superseded by widespread upregulation of epidermal differentiation-related proteins. Both nuclear factor kappa B phosphorylation and GATA3 upregulation was associated with this switch, and GATA3 overexpression was sufficient to increase keratin 1 expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Taken together, these data define a dual role for TLR2 activation during epidermal barrier repair that may be a useful therapeutic modality in treating diseases of epidermal barrier dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bjd\/ljad095","type":"journal-article","created":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T13:35:17Z","timestamp":1679924117000},"page":"91-102","source":"Crossref","is-referenced-by-count":8,"title":["Chronic activation of Toll-like receptor 2 induces an ichthyotic skin 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Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehad","family":"Youssef","sequence":"additional","affiliation":[{"name":"Centre for Cell Biology and Cutaneous Research, Queen Mary University of London , London , UK"},{"name":"Livingstone Skin Research Centre"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-8760","authenticated-orcid":false,"given":"Wendy","family":"Heywood","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0763-8288","authenticated-orcid":false,"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5392-0327","authenticated-orcid":false,"given":"John I","family":"Harper","sequence":"additional","affiliation":[{"name":"Livingstone Skin Research Centre"},{"name":"Department of Immunobiology and Dermatology, UCL Great Ormond Street Institute of Child Health , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3701-0267","authenticated-orcid":false,"given":"Ryan F L","family":"O\u2019Shaughnessy","sequence":"additional","affiliation":[{"name":"Centre for Cell Biology and Cutaneous Research, Queen Mary University of London , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,27]]},"reference":[{"key":"2023100915264656100_ljad095-B1","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jaad.2009.11.020","article-title":"Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sor\u00e8ze 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