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Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo
BACKGROUND: Psoriasis is one of the most frequent skin diseases world-wide. The disease impacts enormously on affected patients and poses a huge financial burden on health care providers. Several lines of evidence suggest that the nuclear hormone receptor peroxisome proliferator activator (PPAR) β/δ...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838790/ https://www.ncbi.nlm.nih.gov/pubmed/20300524 http://dx.doi.org/10.1371/journal.pone.0009701 |
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author | Romanowska, Malgorzata Reilly, Louise Palmer, Colin N. A. Gustafsson, Mattias C. U. Foerster, John |
author_facet | Romanowska, Malgorzata Reilly, Louise Palmer, Colin N. A. Gustafsson, Mattias C. U. Foerster, John |
author_sort | Romanowska, Malgorzata |
collection | PubMed |
description | BACKGROUND: Psoriasis is one of the most frequent skin diseases world-wide. The disease impacts enormously on affected patients and poses a huge financial burden on health care providers. Several lines of evidence suggest that the nuclear hormone receptor peroxisome proliferator activator (PPAR) β/δ, known to regulate epithelial differentiation and wound healing, contributes to psoriasis pathogenesis. It is unclear, however, whether activation of PPARβ/δ is sufficient to trigger psoriasis-like changes in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemistry, we define the distribution of PPARβ/δ in the skin lesions of psoriasis. By expression profiling, we confirm that PPARβ/δ is overexpressed in the vast majority of psoriasis patients. We further establish a transgenic model allowing inducible activation of PPARβ/δ in murine epidermis mimicking its distribution in psoriasis lesions. Upon activation of PPARβ/δ, transgenic mice sustain an inflammatory skin disease strikingly similar to psoriasis, featuring hyperproliferation of keratinocytes, dendritic cell accumulation, and endothelial activation. Development of this phenotype requires the activation of the Th17 subset of T cells, shown previously to be central to psoriasis. Moreover, gene dysregulation in the transgenic mice is highly similar to that in psoriasis. Key transcriptional programs activated in psoriasis, including IL1-related signalling and cholesterol biosynthesis, are replicated in the mouse model, suggesting that PPARβ/δ regulates these transcriptional changes in psoriasis. Finally, we identify phosphorylation of STAT3 as a novel pathway activated by PPARβ/δ and show that inhibition of STAT3 phosphorylation blocks disease development. CONCLUSIONS: Activation of PPARβ/δ in the epidermis is sufficient to trigger inflammatory changes, immune activation, and signalling, and gene dysregulation characteristic of psoriasis. |
format | Text |
id | pubmed-2838790 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-28387902010-03-19 Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo Romanowska, Malgorzata Reilly, Louise Palmer, Colin N. A. Gustafsson, Mattias C. U. Foerster, John PLoS One Research Article BACKGROUND: Psoriasis is one of the most frequent skin diseases world-wide. The disease impacts enormously on affected patients and poses a huge financial burden on health care providers. Several lines of evidence suggest that the nuclear hormone receptor peroxisome proliferator activator (PPAR) β/δ, known to regulate epithelial differentiation and wound healing, contributes to psoriasis pathogenesis. It is unclear, however, whether activation of PPARβ/δ is sufficient to trigger psoriasis-like changes in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemistry, we define the distribution of PPARβ/δ in the skin lesions of psoriasis. By expression profiling, we confirm that PPARβ/δ is overexpressed in the vast majority of psoriasis patients. We further establish a transgenic model allowing inducible activation of PPARβ/δ in murine epidermis mimicking its distribution in psoriasis lesions. Upon activation of PPARβ/δ, transgenic mice sustain an inflammatory skin disease strikingly similar to psoriasis, featuring hyperproliferation of keratinocytes, dendritic cell accumulation, and endothelial activation. Development of this phenotype requires the activation of the Th17 subset of T cells, shown previously to be central to psoriasis. Moreover, gene dysregulation in the transgenic mice is highly similar to that in psoriasis. Key transcriptional programs activated in psoriasis, including IL1-related signalling and cholesterol biosynthesis, are replicated in the mouse model, suggesting that PPARβ/δ regulates these transcriptional changes in psoriasis. Finally, we identify phosphorylation of STAT3 as a novel pathway activated by PPARβ/δ and show that inhibition of STAT3 phosphorylation blocks disease development. CONCLUSIONS: Activation of PPARβ/δ in the epidermis is sufficient to trigger inflammatory changes, immune activation, and signalling, and gene dysregulation characteristic of psoriasis. Public Library of Science 2010-03-16 /pmc/articles/PMC2838790/ /pubmed/20300524 http://dx.doi.org/10.1371/journal.pone.0009701 Text en Romanowska et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Romanowska, Malgorzata Reilly, Louise Palmer, Colin N. A. Gustafsson, Mattias C. U. Foerster, John Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title | Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title_full | Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title_fullStr | Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title_full_unstemmed | Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title_short | Activation of PPARβ/δ Causes a Psoriasis-Like Skin Disease In Vivo |
title_sort | activation of pparβ/δ causes a psoriasis-like skin disease in vivo |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838790/ https://www.ncbi.nlm.nih.gov/pubmed/20300524 http://dx.doi.org/10.1371/journal.pone.0009701 |
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