Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling
Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling
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DOI：
10.1016/j.jaci.2016.08.029
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发表时间：
2017-02-01
影响因子：
14.2
通讯作者：
Guttman-Yassky, Emma
中科院分区：
文献类型：
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作者：
Ewald, David A.;Noda, Shinji;Guttman-Yassky, Emma
背景：特应性皮炎（AD）是由免疫和屏障异常之间复杂的相互作用引起的。AD的鼠模型对于新治疗的临床前评估是必不可少的。虽然许多模型已被用于模拟AD，但它们的转录组学特征尚未完全了解，并且缺乏这些模型与人类AD转录组学指纹的比较。目的：我们试图评估6种常见的小鼠模型的转录组学概况，并确定它们如何与人类AD skin.Methods：转录组学分析进行了使用微阵列和定量RT-PCR活检标本从NC/Nga，长尾，Flg突变，卵白蛋白的挑战，恶唑酮的挑战，和IL-23注射小鼠。AD、银屑病和接触性皮炎患者的基因表达数据来自既往患者队列。2倍或更大的变化和0.05或更小的错误发现率的标准被用于基因arrais.Results：IL-23注射，NC/Nga，和恶唑酮攻击的小鼠表现出最大的同源性与我们的人类荟萃分析得出的AD转录组（37%，18%，17%，分别）。与人AD相似，在注射IL-23的小鼠和NC/Nga小鼠中观察到强烈的T（H）1、T（H）2以及T（H）17活化，在卵清蛋白激发的小鼠中具有相似但较弱的炎症。恶唑酮激发的小鼠表现出以TH 1为中心的反应，而长尾小鼠表现出强烈的TH 17极化。Flg突变的小鼠显示聚丝蛋白下调没有显着inflammation.Conclusion：没有一个单一的小鼠模型完全捕获的AD档案的所有方面，相反，每个模型反映了不同的免疫或屏障疾病方面。总体而言，在6种鼠模型中，IL-23注射小鼠最能模拟人AD;然而，研究的转化重点应确定哪种模型最适用。
Background: Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. Objective: We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin.Methods: Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg-mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23-injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays.Results: IL-23-injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysisderived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust T(H)1, T(H)2, and also T(H)17 activation are seen in IL-23-injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH1-centered reaction, and flaky tail mice demonstrate a strong TH17 polarization. Flg-mutated mice display filaggrin downregulation without significant inflammation.Conclusion: No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23-injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.