Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109.
J Immunol. 2019 Apr 1;202(7):2121-2130. doi: 10.4049/jimmunol.1800650. Epub 2019 Feb 11.
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 (, , and ) 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 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.
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，其中 70%的患者会出现毁容性皮肤炎症（归类为皮肤红斑狼疮[CLE]）。SLE 的治疗选择有限，没有获得美国食品和药物管理局批准的 CLE 治疗方法。研究表明，IFNs 是 SLE 和 CLE 的重要介质，但 IFN 导致疾病的机制仍知之甚少。我们旨在研究 SLE 角质形成细胞中的 IFN 反应如何导致 CLE 的发生。分析了来自 14 个人（7 名 SLE 患者和 7 名健康对照者）的 72 个 RNA 测序样本，以研究 I 型和 II 型 IFN 对 SLE 与对照角质形成细胞的转录组效应。对 IFN 反应进行了深入分析。进行了生物信息学和功能测定，为 IFN 反应变化提供了启示。在狼疮角质形成细胞中鉴定出对 IFNs 的显著超敏反应，包括 SLE 易感性基因座中包含的基因（、和）。转录因子 PITX1 的结合位点在表现出 IFN 敏感反应的基因中富集。基于免疫组织化学，我们发现 CLE 病变中 PITX1 表达增加，通过使用小干扰 RNA 敲低，我们说明在体外上调 IFN 调节基因需要。SLE 患者的皮肤中 IFN 特征增加是由于产生增加和由 PITX1 调节的强烈、偏斜的 IFN 反应。针对这些夸张的途径可能有助于预防和治疗 SLE 皮肤的过度炎症反应。
