Immunomodulatory mechanisms of E-FABP in psoriasis pathogenesis

总结 银屑病是最常见和最难治的免疫介导的慢性炎症性皮肤病。显然 皮肤组织中的树突状细胞（DCs）和角质形成细胞在皮肤炎的发病机制中起着重要作用， 银屑病本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），已被鉴定为代谢和炎症的关键调节剂， 途径。我们的初步研究表明，E-FABP在皮肤组织中的表达大大上调， 牛皮癣患者有趣的是，E-FABP的缺乏赋予了对咪喹莫特（IMQ）或IL-23- 1的保护。 在小鼠模型中诱导银屑病样炎症。虽然肥胖与严重程度增加有关， 银屑病和治疗反应差，肥胖和银屑病之间的潜在机制是 未知虽然高脂饮食（HFD）增加DCs和角质形成细胞中E-FABP的表达， 肥胖相关的慢性皮肤炎症在野生型小鼠中，E-FABP缺乏保护小鼠免受HFD- 诱导效应。以上结果提示E-FABP可能通过调节机体代谢而与银屑病发病相关 以及DC和角质形成细胞的功能。因此，我们假设，E-FABP，作为一个新的联系， 肥胖-银屑病相关，通过增强细胞代谢促进银屑病发病， DC和角质形成细胞的功能。因此，靶向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的代谢和功能。我们假设E-FABP链接 DC中FA代谢和先天免疫信号传导，以及先天性和适应性免疫应答的桥梁， 银屑病发病机制特异性目的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 在角质形成细胞中的表达介导先天信号诱导的代谢变化，这些变化对于异常 角质形成细胞分化具体目标3将检查E-FABP是否与肥胖/银屑病相关 使用我们独特的E-FABP全局和条件性敲除小鼠模型和来自 牛皮癣患者总之，该提议将证明E-FABP促进细胞凋亡的新机制。 银屑病的发病机制与肥胖相关的银屑病的发展有关。因此，靶向E-FABP可以提供 一种治疗银屑病和其它炎性皮肤病的新策略。

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.