Characterization of Interferon Kappa as a Novel Target in Cutaneous Lupus

干扰素 Kappa 作为皮肤狼疮新靶点的表征

• 批准号: 10238899
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 33.23万
• 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: 2017-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238899
• 关键词: Address; Agonist; Autoimmunity; CCL2 gene; Cells; Cutaneous; Cutaneous Lupus Erythematosus; Data; Dendritic Cells; Development; Disease; Epidermis; Epithelial; Flare; Fostering; Future; Goals; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Interleukin-6; Investigation; Lead; Lesion; Leucocytic infiltrate; Lupus; Methylation; Mission; Modeling; Mus; Myeloid Cells; Organ; Pathogenesis; Patients; Population; Prevention; Prevention strategy; Production; Public Health; Quality of life; Regulation; Research; Role; Signal Transduction; Skin; Source; Stimulus; Systemic Lupus Erythematosus; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Ultraviolet B Radiation; Ultraviolet Rays; United States National Institutes of Health; Work; autocrine; chemokine; cytokine; disability; genetic risk factor; improved; in vivo; keratinocyte; lupus cutaneous; microbial; monocyte; novel; overexpression; prevent; promoter; recruit; response; side effect; skin disorder; skin lesion; systemic autoimmunity; targeted treatment; therapeutic development; treatment strategy

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.

抽象的 皮肤红斑狼疮（CLE）病变中的I型干扰素（IFN）增加了 疾病的发病机理，但尚未探索I型IFN的皮肤内部源。角质形成细胞是 IFN Kappa（κ）的主要来源，I型IFN是皮肤狼疮的遗传风险因素，显着 在CLE皮肤病变中上调，并从系统性的红斑狼疮（SLE）VS中更坚固地产生。 控制角质形成细胞。重要的是，IFNκ信号传导的中和消除了对 SLE角质形成细胞中的紫外线光和类似收费的受体激动剂。那，IFNκ素质丰富的皮肤 SLE中的炎症反应。因此，了解IFNκ的调节及其在 调节炎症性细胞因子的产生和细胞浸润的募集，因为IFNκ可能被证明是一种 因此，特定的治疗或预防皮肤病变及其特定抑制作用可能 避免对其他I型IFN的全身封锁副作用。该项目的总体目标是定义 SLE皮肤中IFNκ异常调节的机制和后果。假设超级 IFNκ的产生是SLE角质形成细胞的机制，以过度产生炎症 细胞因子和趋化因子，因此增加炎症反应，因此IFNκ将因此作为 预防或治疗与SLE相关的皮肤病变的特定靶标。提案将 通过调查以下研究来解决这一假设：目标1：确定基本机制 狼疮角质形成细胞中IFNκ的产生增加。通过IFN对IFNκ进行调节，刺激信号和 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。目标2：确定角质形成细胞产生的IFNκ促进的机制 炎症反应。 IFNκ对角质形成细胞IFN产生的影响，单核细胞，树突细胞和 将探索质囊性树突状细胞募集和体外激活。目标3：确定 IFNκ过表达对皮肤注射和全身自身免疫的体内影响。 皮肤和全身自身免疫的表征以及对皮肤炎症刺激的反应 在一种过表达表皮中IFNκ的新型小鼠中完成。这项工作的完成将支持 角质形成细胞衍生的IFNκ被认为是启动和 SLE皮肤中超炎反应的持续性，被确定为未来的特定目标 治疗和预防与SLE相关的皮肤病变。