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: 10004499
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 34.53万
• 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/10004499
• 关键词: Address; Agonist; Autoimmunity; CCL2 gene; Cells; Cutaneous; Cutaneous Lupus Erythematosus; Data; Dendritic Cells; Development; Disease; Epidermis; Epithelial; Epithelium; 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.

摘要 I型干扰素（IFN）在皮肤红斑狼疮（CLE）病变中增加， 疾病的发病机制，但皮肤内源性来源的I型IFN还没有探索。角质细胞是 IFN κ（κ）的主要来源，一种I型IFN，是皮肤狼疮的遗传危险因素， 在CLE皮肤病变中上调，并且从系统性红斑狼疮（SLE）vs. 对照角质形成细胞。重要的是，IFNκ信号传导的中和消除了过度炎症反应， 紫外线和Toll样受体激动剂在SLE角质形成细胞中的作用。因此，IFNκ启动了丰富的皮肤 SLE炎症反应。因此，了解IFNκ的调节及其在细胞内的作用是至关重要的。 调节炎症细胞因子的产生和细胞浸润的募集，如IFNκ可能被证明是一种免疫调节因子。 治疗或预防皮肤损伤特异性靶点，其特异性抑制因此可 避免其他I型IFN系统性阻断的副作用。本项目的总体目标是确定 SLE皮肤中IFNκ异常调节的机制和后果。据推测，超- IFNκ的产生是SLE角质形成细胞过度产生炎性因子的机制， 细胞因子和趋化因子，并因此增加炎症反应，IFNκ因此将作为 预防或治疗SLE相关皮肤病变的特异性和可行的靶点。该提案将 通过以下研究解决这一假设：目标1：确定潜在的机制 增加狼疮角质形成细胞中IFNκ的产生。IFNκ通过IFN、STING信号传导的调节和 将在对照和SLE中探索甲基化变化（包括考虑CLE亚型） 角质形成细胞目的2：确定角质形成细胞产生的IFNκ促进 炎症反应。IFNκ对角质形成细胞IFN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活化。目标3：确定 IFNκ过表达对皮肤炎症和系统性自身免疫体内影响 皮肤和全身自身免疫的特征以及对皮肤炎症刺激的反应将 在一种新的小鼠中完成，该小鼠在表皮中过表达IFNκ。这项工作的完成将有助于 一种范式转变，其中角质形成细胞衍生的IFNκ被认为是引发的重要步骤， 持续的高度炎症反应的SLE皮肤，并确定为一个特定的目标， 治疗和预防SLE相关的皮肤病变。