Activation of PPARbeta/delta causes a psoriasis-like skin disease in vivo.
Activation of PPARbeta/delta causes a psoriasis-like skin disease in vivo.
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DOI：
10.1371/journal.pone.0009701
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发表时间：
2010-03-16
期刊：
影响因子：
3.7
通讯作者：
Foerster J
中科院分区：
文献类型：
--
作者：
Romanowska M;Reilly L;Palmer CN;Gustafsson MC;Foerster J
牛皮癣是世界范围内最常见的皮肤病之一。这种疾病对受影响的患者影响巨大，并给医疗保健提供者带来巨大的经济负担。多项证据表明，已知可调节上皮分化和伤口愈合的核激素受体过氧化物酶体增殖物激活剂 (PPAR) β/δ 有助于银屑病的发病机制。然而，目前尚不清楚 PPARβ/δ 的激活是否足以引发体内银屑病样变化。使用免疫组织化学，我们确定了 PPARβ/δ 在银屑病皮损中的分布。通过表达谱分析，我们证实 PPARβ/δ 在绝大多数银屑病患者中过度表达。我们进一步建立了一个转基因模型，允许 PPARβ/δ 在小鼠表皮中诱导激活，模拟其在银屑病病变中的分布。 PPARβ/δ 激活后，转基因小鼠会患上与牛皮癣极为相似的炎症性皮肤病，其特点是角质形成细胞过度增殖、树突状细胞积聚和内皮细胞激活。这种表型的形成需要 T 细胞的 Th17 子集的激活，之前的研究表明，该子集是银屑病的核心。此外，转基因小鼠的基因失调与牛皮癣高度相似。银屑病中激活的关键转录程序，包括 IL1 相关信号传导和胆固醇生物合成，在小鼠模型中得到复制，表明 PPARβ/δ 调节银屑病中的这些转录变化。最后，我们确定 STAT3 磷酸化是 PPARβ/δ 激活的一种新途径，并表明抑制 STAT3 磷酸化可阻止疾病发展。表皮中 PPARβ/δ 的激活足以引发炎症变化、免疫激活、信号传导以及银屑病特征的基因失调。
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. 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. Activation of PPARβ/δ in the epidermis is sufficient to trigger inflammatory changes, immune activation, and signalling, and gene dysregulation characteristic of psoriasis.
DOI：
10.1083/jcb.1866if
发表时间：
2009-09-21
期刊：
The Journal of Cell Biology
影响因子：
--
作者：
Short B
通讯作者：
Short B