Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus

摘要 I型干扰素(IFN)在皮肤红斑狼疮(CLE)皮损中增加，并有助于 该病的发病机制尚不清楚，但I型干扰素的皮肤内源性来源尚不清楚。角质形成细胞是 干扰素kappa(κ)的主要来源，这是一种I型干扰素，是皮肤狼疮的遗传风险因素，显著 在CLE皮肤病变中上调，在系统性红斑狼疮(SLE)比 控制角质形成细胞。重要的是，干扰素κ信号的中和消除了对 紫外线和Toll样受体激动剂在系统性红斑狼疮角质形成细胞中的作用。因此，干扰素κ启动丰富的皮肤 系统性红斑狼疮的炎症反应。因此，了解干扰素κ的调节及其在 干扰素κ对炎性细胞因子产生和细胞浸润募集的调节可能被证明是一种 用于治疗或预防皮肤损害的特定靶点，以及其特定抑制因此可以 避免其他I型IFN的全身性阻断的副作用。该项目的总体目标是定义 干扰素κ在系统性红斑狼疮皮肤中异常调节的机制和后果。据推测，超- 干扰素κ的产生是系统性红斑狼疮角质形成细胞过度产生炎症的一种机制 细胞因子和趋化因子，从而增加炎症反应，因此干扰素κ将作为 预防或治疗系统性红斑狼疮相关皮肤损害的特定和可行的靶点。这项提议将 通过调查以下内容来解决这一假设：目标1：确定潜在的机制 狼疮角质形成细胞产生干扰素κ增加。干扰素κ受干扰素、STIN信号和转录因子的调节 将在对照和SLE中探索甲基化变化(包括考虑CLE亚型)。 角质形成细胞。目的2：确定角质形成细胞产生的干扰素κ促进 炎症反应。干扰素κ对角质形成细胞干扰素产生、单核细胞、树突状细胞和 将探索浆细胞样树突状细胞在体外和体内的募集和激活。目标3：确定 干扰素κ过表达对皮肤炎症和全身自身免疫的影响。 皮肤和全身自身免疫的特征以及对皮肤炎症刺激的反应 在一种在表皮过度表达干扰素κ的新型小鼠中完成。这项工作的完成将支持 一种范式的转变，角质形成细胞来源的干扰素κ被认为是启动和 系统性红斑狼疮皮肤中高炎症反应的持续性，并被确定为未来的特定靶点 系统性红斑狼疮相关皮损的治疗和预防。

ABSTRACT Type I interferons (IFNs) are increased in cutaneous lupus erythematosus (CLE) lesions and contribute to disease pathogenesis, yet skin-intrinsic sources of type I IFN have not been explored. Keratinocytes are the primary source of IFN kappa (κ), a type I IFN that is a genetic risk factor for cutaneous lupus, significantly upregulated in CLE skin lesions, and is produced more robustly from systemic lupus erythematosus (SLE) vs. control keratinocytes. Importantly, neutralization of IFNκ signaling eliminates hyper-inflammatory responses to ultraviolet light and toll-like receptor agonists in SLE keratinocytes. Thus, IFNκ primes the abundant cutaneous inflammatory response in SLE. It is consequently critical to understand the regulation of IFNκ and its role in regulation of inflammatory cytokine production and recruitment of cellular infiltrates as IFNκ may prove to be a specific target for treatment or prevention of cutaneous lesions, and its specific inhibition may consequently avoid side effects from systemic blockade of other type I IFNs. The overall objective for this project is to define the mechanisms and consequences of aberrant regulation of IFNκ in SLE skin. It is hypothesized that hyper- production of IFNκ is a mechanism by which SLE keratinocytes are primed to overproduce inflammatory cytokines and chemokines and consequently increase inflammatory responses and that IFNκ will thus serve as a specific and viable target for prevention or treatment of SLE-associated skin lesions. The proposal will address this hypothesis through investigation of the following: Aim 1: Identify the mechanisms underlying increased production of IFNκ in lupus keratinocytes. Regulation of IFNκ by IFNs, STING signaling and methylation changes will be explored in control and SLE (including consideration of CLE subtypes) keratinocytes. Aim 2: Identify the mechanisms by which keratinocyte-produced IFNκ promotes inflammatory responses. Effects of IFNκ on keratinocyte IFN production, monocyte, dendritic cell, and plasmacytoid dendritic cell recruitment and activation in vitro and in vivo will be explored. Aim 3: Identify the in vivo impact of IFNκ overexpression on cutaneous inflammation and systemic autoimmunity. Characterization of cutaneous and systemic autoimmunity and response to cutaneous inflammatory stimuli will be completed in a novel mouse that overexpresses IFNκ in the epidermis. Completion of this work will support a paradigm shift in which keratinocyte-derived IFNκ is recognized as an important step for priming and persistence of a hyper-inflammatory response in SLE skin and is identified as a specific target for future treatment and prevention of SLE-associated skin lesions.