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: 9761987
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 39.06万
• 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/9761987
• 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 I 型干扰素 (IFN) 在皮肤红斑狼疮 (CLE) 病变中增加，并有助于 疾病发病机制，但 I 型干扰素的皮肤内在来源尚未被探索。角质形成细胞是 IFN kappa (κ) 的主要来源，这是一种 I 型 IFN，是皮肤狼疮的遗传危险因素，显着 在 CLE 皮肤病变中表达上调，并且与系统性红斑狼疮 (SLE) 相比，其产生更为强烈。 控制角质形成细胞。重要的是，IFNκ信号传导的中和消除了过度炎症反应 SLE 角质形成细胞中的紫外线和 Toll 样受体激动剂。因此，IFNκ启动丰富的皮肤 SLE 中的炎症反应。因此，了解 IFNκ 的调节及其在疾病中的作用至关重要。 调节炎症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 治疗或预防皮肤病变的特定靶点，及其特异性抑制可能因此 避免其他 I 型干扰素的全身阻断产生的副作用。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。据推测，超 IFNκ 的产生是 SLE 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，IFNκ 将因此充当 预防或治疗 SLE 相关皮肤病变的具体且可行的目标。该提案将 通过调查以下内容来解决这一假设： 目标 1：确定潜在机制 狼疮角质形成细胞中 IFNκ 的产生增加。 IFNκ 通过 IFN、STING 信号传导和 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、单核细胞、树突状细胞和 将探索体外和体内浆细胞样树突状细胞的招募和激活。目标 3：确定 IFNκ过表达对皮肤炎症和全身自身免疫的体内影响。 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 该研究是在表皮过度表达 IFNκ 的新型小鼠中完成的。这项工作的完成将支持 一种范式转变，其中角质形成细胞衍生的 IFNκ 被认为是启动和 SLE 皮肤中持续存在的高炎症反应，被确定为未来的具体目标 治疗和预防 SLE 相关的皮肤病变。