Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus
Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus
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DOI：
10.4049/jimmunol.1800650
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发表时间：
2019-04-01
影响因子：
4.4
通讯作者：
Kahlenberg, J. Michelle
中科院分区：
文献类型：
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作者：
Tsoi, Lam C.;Hile, Grace A.;Kahlenberg, J. Michelle
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，其中70%的患者经历毁容性皮肤炎症（归类于皮肤红斑狼疮[CLE]的标题下）。SLE的治疗选择有限，并且没有食品和药物管理局批准的CLE疗法。研究表明，IFN是SLE和CLE的重要介质，但IFN导致疾病的机制仍然知之甚少。我们的目的是研究SLE角质形成细胞中的IFN应答如何促进CLE的发展。分析了来自14个个体（7个SLE和7个健康对照）的72个RNA测序样品的队列，以研究I型和II型IFN对SLE相对于对照角质形成细胞的转录组学效应。对IFN应答进行了深入分析。生物信息学和功能分析进行了IFN反应的变化提供的影响。在狼疮角质形成细胞中发现了对IFN的显著过敏反应，包括SLE易感基因座中包含的基因（IFIH 1、STAT 1和IRF 7）。转录因子PITX 1的结合位点在表现出IFN敏感性反应的基因中富集。PITX 1表达增加CLE病变的基础上，免疫组化，并通过使用小干扰RNA敲低，我们说明，PITX 1是所需的IFN-调节基因在体外上调。SLE患者在其皮肤中表现出增加的IFN特征，继发于增加的产生和由PITX 1调节的稳健的、偏斜的IFN应答。靶向这些夸张的途径可能被证明是有益的，以预防和治疗SLE皮肤的炎症反应。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which 70% of patients experience disfiguring skin inflammation (grouped under the rubric of cutaneous lupus erythematosus [CLE]). There are limited treatment options for SLE and no Food and Drug Administration approved therapies for CLE. Studies have revealed that IFNs are important mediators for SLE and CLE, but the mechanisms by which IFNs lead to disease are still poorly understood. We aimed to investigate how IFN responses in SLE keratinocytes contribute to development of CLE. A cohort of 72 RNA sequencing samples from 14 individuals (seven SLE and seven healthy controls) were analyzed to study the transcriptomic effects of type I and type II IFNs on SLE versus control keratinocytes. In-depth analysis of the IFN responses was conducted. Bioinformatics and functional assays were conducted to provide implications for the change of IFN response. A significant hypersensitive response to IFNs was identified in lupus keratinocytes, including genes (IFIH1, STAT1, and IRF7) encompassed in SLE susceptibility loci. Binding sites for the transcription factor PITX1 were enriched in genes that exhibit IFN-sensitive responses. PITX1 expression was increased in CLE lesions based on immunohistochemistry, and by using small interfering RNA knockdown, we illustrated that PITX1 was required for upregulation of IFN-regulated genes in vitro. SLE patients exhibit increased IFN signatures in their skin secondary to increased production and a robust, skewed IFN response that is regulated by PITX1. Targeting these exaggerated pathways may prove to be beneficial to prevent and treat hyperinflammatory responses in SLE skin.