Identification of BATF2 as a Regulator of Interferon-Enhanced Inflammatory Responses in Lupus Skin

鉴定 BATF2 作为狼疮皮肤中干扰素增强炎症反应的调节剂

• 批准号: 9375222
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 7.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375222
• 关键词: Apoptotic; Binding; Biology; Cells; ChIP-seq; Cutaneous; Cutaneous Lupus Erythematosus; Data; Development; Discoid Lupus Erythematosus; Disease; Exhibits; Family; Flare; Fostering; Funding; Gene Expression Regulation; Genes; Goals; IRF1 gene; Immunoprecipitation; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interferon-alpha; Interferons; Interleukin-6; Lead; Lesion; Lupus; Mainstreaming; Mediating; Mediator of activation protein; Microscopy; Mission; Mus; Myeloid Cells; Nuclear; Organ; Pathogenesis; Patients; Phenotype; Play; Production; Public Health; Recruitment Activity; Regulation; Research; Role; Signal Transduction; Skin; Small Interfering RNA; Stimulus; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Time; Transcription Factor AP-1; Transcriptional Regulation; Ultraviolet B Radiation; Ultraviolet Rays; United States National Institutes of Health; Up-Regulation; career; chemokine; cofactor; cytokine; disability; improved; in vivo; innovation; keratinocyte; knock-down; lupus cutaneous; novel; novel therapeutics; overexpression; prevent; response; skin disorder; therapeutic development; therapeutic target; therapy outcome; transcription factor; transcriptome sequencing

ABSTRACT/PROJECT SUMMARY Cutaneous inflammation is a prevalent and often difficult to treat manifestation of systemic lupus erythematosus (SLE) that is frequently associated with and may lead to exacerbation of systemic disease. There is a critical need to understand the mechanisms behind why SLE skin is prone to inflammation in order to improve therapies and outcomes for skin disease patients. Type I interferon (IFN) responses are elevated in cutaneous lupus erythematosus (CLE) lesions and prime keratinocytes for inflammatory responses to ultraviolet light exposure. Importantly, SLE keratinocytes display an exaggerated response to IFNα for some, but not all, type I IFN regulated genes. These SLE-IFN-skewed genes likely play a critical role in promoting the enhanced inflammatory response in SLE keratinocytes One of these SLE-IFN-skewed genes is BATF2, an understudied transcription factor that interacts with interferon regulatory factor 1 (IRF-1) to regulate inflammatory gene production. These preliminary data suggest that BATF2 may serve as an excellent target to modulate inflammatory responses in the skin and thus to prevent and treat cutaneous inflammation in SLE. We hypothesize that exaggerated inflammatory responses in SLE keratinocytes are driven through IFN- mediated hyper-upregulation of BATF2. Testing of this hypothesis through the following Aims will identify a mechanism by which IFNs promote inflammatory signaling in SLE keratinocytes and identify BATF2 as a potential therapeutic target for controlling cutaneous inflammation in SLE Aim 1: Identify BATF2 as a crucial mediator of pro-inflammatory cytokines and chemokines following type I IFN priming of keratinocytes. Aim 2: Identify the role of BATF2 in regulation of type I vs. type II IFN responses in keratinocytes and how this is regulated by IRFs. Completion of these Aims will identify BATF2 as a regulator of inflammatory responses in keratinocytes and as a target for decreasing keratinocyte-derived inflammation in lupus skin. Further, this project will compare how type I and type II IFNs, both of which are identified as important in SLE skin, induce inflammatory changes through BATF2. This information will have important implications as type I IFN-directed therapy becomes mainstream in SLE.

摘要/项目总结 皮肤炎症是一种普遍的，往往难以治疗的表现系统性狼疮 红斑性狼疮（SLE）通常与全身性疾病相关并可能导致全身性疾病恶化。 目前迫切需要了解SLE皮肤易发生炎症的机制， 以改善皮肤病患者的治疗和结果。I型干扰素（IFN）应答在以下患者中升高： 皮肤红斑狼疮（CLE）病变和初级角质形成细胞的炎症反应， 紫外线照射。重要的是，SLE角质形成细胞对IFNα表现出过度反应， 但不是全部I型IFN调节基因。这些SLE-IFN倾向的基因可能在促进SLE发病方面发挥着关键作用。 SLE角质形成细胞中增强的炎症反应这些SLE-IFN-偏斜基因之一是BATF 2， 一种未充分研究的转录因子，与干扰素调节因子1（IRF-1）相互作用， 炎症基因的产生。这些初步数据表明，BATF 2可能是一个很好的靶点， 调节皮肤中的炎症反应，从而预防和治疗SLE中的皮肤炎症。我们 假设SLE角质形成细胞中过度的炎症反应是通过IFN-γ驱动的， 介导的BATF 2的过度上调。通过以下目的对这一假设进行检验， IFN促进SLE角质形成细胞炎症信号传导的机制，并将BATF 2鉴定为 控制SLE皮肤炎症的潜在治疗靶点目的1：确定BATF 2作为一个关键的 I型IFN引发角质形成细胞后促炎细胞因子和趋化因子的介导物。 目的2：确定BATF 2在角质形成细胞中调节I型与II型IFN应答中的作用， 这是如何由IRF监管的。这些目标的完成将确定BATF 2作为炎症调节因子， 作为减少狼疮皮肤中角化细胞衍生的炎症的靶点。 此外，该项目将比较I型和II型干扰素，这两种干扰素在SLE中被确定为重要的 皮肤，通过BATF 2诱导炎症变化。这一信息将具有重要的意义， IFN导向治疗成为SLE的主流。