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

摘要/项目摘要 皮肤炎是系统性红斑狼疮的一种常见且通常难以治疗的表现。 红斑狼疮(SLE)，通常与系统性疾病有关，并可能导致系统性疾病的恶化。 迫切需要了解系统性红斑狼疮皮肤容易发炎的机制 以改善皮肤病患者的治疗方法和结果。I型干扰素(干扰素)反应在 皮肤红斑狼疮(CLE)皮损和原始角质形成细胞对炎症反应的影响 紫外线照射。重要的是，系统性红斑狼疮角质形成细胞对干扰素α表现出夸大的反应， 但不是全部，I型干扰素调控的基因。这些偏斜的SLE-干扰素基因可能在促进 系统性红斑狼疮角质形成细胞炎症反应增强其中一个基因是BATF2，一种 未被研究的与干扰素调节因子1(IRF-1)相互作用的转录因子 炎性基因的产生。这些初步数据表明，BATF2可能是一个很好的靶标 调节皮肤的炎症反应，从而预防和治疗系统性红斑狼疮的皮肤炎症。我们 假设系统性红斑狼疮角质形成细胞的炎症反应是通过干扰素驱动的。 介导的BATF2基因高表达。通过以下目标对这一假设进行测试将确定 干扰素促进系统性红斑狼疮角质形成细胞炎症信号转导机制的研究 控制系统性红斑狼疮皮肤炎症的潜在治疗靶点目标1：确定BATF2是至关重要的 I型干扰素刺激角质形成细胞后的促炎细胞因子和趋化因子的介体。 目的2：确定BATF2在角质形成细胞中调节I型和II型干扰素反应中的作用 这是如何受到IRF的监管的。这些目标的完成将使BATF2成为炎症的调节因子 角质形成细胞的反应，并作为减少狼疮皮肤角质形成细胞源性炎症的靶点。 此外，本项目将比较I型和II型IFN，这两种类型的IFN在SLE中都被认为是重要的 皮肤，通过BATF2诱导炎症变化。这一信息将具有重要的影响，因为类型I 干扰素导向治疗成为系统性红斑狼疮治疗的主流。

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.