Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis

E-FABP在银屑病发病机制中的免疫调节机制

• 批准号: 10459902
• 负责人: Bing Li
• 金额: $ 38.64万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459902
• 关键词: Abnormal Keratinocyte; Address; Cell physiology; Cellular Metabolic Process; Chronic; Data; Dendritic Cells; Development; High Fat Diet; Human; Imiquimod; Immune; Immune signaling; Inflammation; Inflammatory; Knockout Mice; Link; Mediating; Metabolic; Metabolism; Mitochondria; Molecular; Mus; Obesity; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Protein Deficiency; Psoriasis; Role; Sampling; Severities; Signal Transduction; Skin; Skin Tissue; Testing; Wild Type Mouse; adaptive immune response; chronic inflammatory skin; conditional knockout; design; diet-induced obesity; experimental study; fatty acid-binding proteins; immunoregulation; innate immune function; interleukin-23; keratinocyte; keratinocyte differentiation; link protein; mouse model; novel; novel strategies; oxidation; protein expression; response; sensor; skin disorder; treatment strategy

Summary Psoriasis is the most prevalent and intractable immune-mediated chronic inflammatory skin disease. It is clear that dendritic cells (DCs) and keratinocytes in the skin tissues play a central role in the pathogenesis of psoriasis. The objectives of this proposal are to determine the role of epidermal fatty acid binding protein (E- FABP) in promoting psoriasis pathogenesis through simultaneously targeting both DCs and keratinocytes and in linking obesity-associated psoriasis development. E-FABP, first cloned in psoriatic skin tissues (also known as psoriasis associated FABP), has been identified as a critical regulator of both metabolic and inflammatory pathways. Our preliminary studies demonstrate that E-FABP is greatly upregulated in the skin tissue from patients with psoriasis. Intriguingly, deficiency of E-FABP confers protection from imiquimod (IMQ) or IL-23- induced psoriasis-like inflammation in mouse models. While obesity is associated with increased severity of psoriasis and poor responses to therapy, the underlying mechanisms between obesity and psoriasis are unknown. While high fat diet (HFD) increases E-FABP expression in both DCs and keratinocytes and promotes obesity-associated chronic skin inflammation in wild type mice, E-FABP deficiency protects mice against HFD- induced effects. All these data suggest that E-FABP may link obesity and psoriasis via regulating metabolism and function of DCs and keratinocytes. Thus, we hypothesize that E-FABP, as a new link underlying the obesity-psoriasis association, promotes psoriasis pathogenesis through enhancing cellular metabolism and function of both DCs and keratinocytes. Therefore, targeting E-FABP may represent a novel strategy for psoriasis therapy. We design three specific aims (Figure A) to address our hypotheses. Specific Aim 1 will address how E-FABP regulates DC metabolism and function in psoriasis. We hypothesize that E-FABP links FA metabolism and innate immune signaling in DCs and bridges innate and adaptive immune responses for psoriasis pathogenesis. Specific Aim 2 will determine how E-FABP promotes keratinocyte aberrant metabolism and differentiation in psoriasis. We will design experiments to test the hypothesis that E-FABP expression in keratinocytes mediates innate signal-induced metabolic changes that are critical for abnormal keratinocyte differentiation. Specific Aim 3 will examine whether E-FABP links the obesity/psoriasis association using our unique E-FABP global and conditional knock out mouse models and samples from psoriasis patients. In summary, this proposal will demonstrate a novel mechanism by which E-FABP promotes psoriasis pathogenesis and links obesity-associated psoriasis development. Thus, targeting E-FABP may offer a novel strategy for treatment of psoriasis and other inflammatory skin disorders.

概括 牛皮癣是最普遍和最难治的免疫介导的慢性炎症性皮肤病。很明显 皮肤组织中的树突状细胞（DC）和角质形成细胞在皮肤病的发病机制中发挥着核心作用 银屑病。该提案的目的是确定表皮脂肪酸结合蛋白（E- FABP）通过同时靶向 DC 和角质形成细胞来促进银屑病发病机制， 与肥胖相关的牛皮癣的发展有关。 E-FABP，首先在银屑病皮肤组织中克隆（也称为 作为银屑病相关的 FABP），已被确定为代谢和炎症的关键调节因子 途径。我们的初步研究表明，E-FABP 在皮肤组织中的表达显着上调 牛皮癣患者。有趣的是，E-FABP 的缺乏可提供对咪喹莫特 (IMQ) 或 IL-23- 的保护。 在小鼠模型中诱导牛皮癣样炎症。虽然肥胖与以下问题的严重程度增加有关： 银屑病和治疗反应不佳，肥胖和银屑病之间的潜在机制是 未知。而高脂肪饮食 (HFD) 会增加 DC 和角质形成细胞中 E-FABP 的表达，并促进 野生型小鼠与肥胖相关的慢性皮肤炎症，E-FABP 缺乏可保护小鼠免受 HFD- 诱发效应。所有这些数据表明 E-FABP 可能通过调节代谢将肥胖与牛皮癣联系起来 以及 DC 和角质形成细胞的功能。因此，我们假设 E-FABP 作为底层的新链接 肥胖-银屑病关联，通过增强细胞代谢和促进银屑病发病机制 DC 和角质形成细胞的功能。因此，针对 E-FABP 可能代表了一种新的策略 牛皮癣治疗。我们设计了三个具体目标（图 A）来解决我们的假设。具体目标 1 将 阐述 E-FABP 如何调节银屑病中 DC 代谢和功能。我们假设 E-FABP 链接 DC 中的 FA 代谢和先天免疫信号传导，并桥接先天和适应性免疫反应 牛皮癣的发病机制。具体目标 2 将确定 E-FABP 如何促进角质形成细胞异常 牛皮癣的代谢和分化。我们将设计实验来检验 E-FABP 的假设 角质形成细胞中的表达介导先天信号诱导的代谢变化，这对于异常 角质细胞分化。具体目标 3 将检查 E-FABP 是否与肥胖/牛皮癣相关 使用我们独特的 E-FABP 全局和条件敲除小鼠模型和样本进行关联 牛皮癣患者。总之，该提案将展示一种 E-FABP 促进的新机制 银屑病发病机制以及与肥胖相关的银屑病发展之间的联系。因此，靶向 E-FABP 可能会提供 治疗牛皮癣和其他炎症性皮肤病的新策略。