Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis

摘要 银屑病是免疫介导的最常见、最难治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红斑狼疮的发病机制中起核心作用。 银屑病。这项建议的目的是确定表皮脂肪酸结合蛋白(E-FBP)的作用。 FABP)通过同时靶向DC和角质形成细胞来促进银屑病的发病 与肥胖相关的牛皮癣的发展有关。E-FABP，最先在银屑病患者皮肤组织中克隆(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 小路。我们的初步研究表明，E-FABP在皮肤组织中显著上调 牛皮癣患者。有趣的是，E-FABP的缺乏提供了对咪喹莫特(Imquimod，ImQ)或IL-23的保护作用。 在小鼠模型中诱导银屑病样炎症。虽然肥胖与高血压严重程度的增加有关 银屑病和治疗反应差，肥胖和银屑病之间的潜在机制是 未知。而高脂饮食(HFD)增加DC和角质形成细胞E-FABP的表达，并促进 野生型小鼠肥胖相关的慢性皮肤炎，E-FABP缺陷可保护小鼠免受HFD- 诱导效应。所有这些数据表明，E-FABP可能通过调节代谢将肥胖和银屑病联系起来 DC和角质形成细胞的功能。因此，我们假设E-FABP作为基础的新链接 肥胖与银屑病的关系，通过增强细胞代谢和促进银屑病的发病机制 树突状细胞和角质形成细胞的功能。因此，瞄准E-FABP可能代表着一种新的战略 牛皮癣治疗。我们设计了三个具体的目标(图A)来解决我们的假设。具体目标1将 阐述E-FABP如何调节银屑病患者的DC代谢和功能。我们假设E-FABP链接 树突状细胞的FA代谢和先天免疫信号，桥接先天和获得性免疫反应 银屑病发病机制。特定目标2将确定E-FABP如何促进角质形成细胞异常 银屑病的代谢和分化。我们将设计实验来验证E-FABP的假设 角质形成细胞的表达介导先天信号诱导的代谢变化，这些变化是异常的关键 角质形成细胞分化。具体目标3将检查E-FABP是否与肥胖/牛皮癣有关 使用我们独特的E-FABP全局和条件基因敲除小鼠模型和样本进行关联 牛皮癣患者。总之，这项提议将展示一种新的机制，E-FABP通过它来促进 银屑病的发病机制与肥胖相关的银屑病的发展有关。因此，针对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。

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.