P2X7R Signaling in Psoriasis Pathogenesis

描述(申请人提供)：牛皮癣是一种皮肤自身免疫性疾病，全世界有多达1.25亿人受到影响。目前银屑病的治疗方法包括全身性免疫抑制药物，其长期效果仍然令人担忧。银屑病是一种依赖于皮肤树突状细胞偏向的辅助性T细胞(Th)17效应细胞的细胞介导的疾病。重要的是，诱导DC和角质形成细胞分泌Th极化细胞因子的刺激因素，特别是在银屑病中，是复杂的，还没有完全了解。在这一背景下，三磷酸腺苷是一个特别吸引人的警报器，它通过P2X7受体(P2X7R)信号诱导NF-κB激活和IL-23/IL-17轴，这两个已被证明是银屑病的易感途径。因此，P2X7R信号将早期炎症触发与银屑病易感因素联系起来。有趣的是，NF-κB还导致了P2X7R表达的维持，形成了正反馈机制。我们正在进行的研究结果支持了目前尚未被认识的P2X7R信号在银屑病发病机制中的作用。具体地说，我们提供的证据表明，在健康的人皮肤中，P2X7R信号诱导先天免疫，刺激DC表达IL-1？、IL-6、IL-23、IL-15和VEGF，并促进Th17偏向。此外，与健康供者相比，银屑病患者皮损和非皮损皮肤中P2X7R的表达增加。这种非皮损皮肤中P2X7R表达的增加代表了银屑病患者皮肤的原发异常，而不是炎症的继发性影响。在这一理论和实验基础的支持下，我们假设在一个遗传易感的微环境中，皮肤P2X7R信号是银屑病发病机制的一个机制，可以作为治疗的靶点。因此，我们在这项临床前提案中的目标是确定P2X7R信号在银屑病皮损的发生和维持中的作用，并阐明可用于银屑病新疗法的新的依赖于P2X7R的致病机制。为了验证我们的新的和创新的假说，我们建立了以下特定的目标：目标1将定义由皮肤P2X7R信号诱导的炎症通路。目的2将在遗传易感的微环境中确定P2X7R信号在银屑病发病机制中的参与，目的3将检验P2X7R拮抗剂减轻银屑病皮损的治疗能力。在小鼠和人类中，ATP和P2X7R信号通路的保守性支持了我们提出的研究的翻译价值，并提供了一个机会，通过结合人类和小鼠的牛皮癣模型来利用一种独特的创新方法。在这项建议的结论中，我们将确定在遗传易感的银屑病微环境中，P2X7R信号是致病的。我们的结果将导致增加科学知识基础，开发一个模型来进一步研究P2X7R信号机制和银屑病的发病机制，并为未来的建议进行新的治疗策略的原则验证研究。

DESCRIPTION (provided by applicant): Psoriasis is a cutaneous autoimmune disease that affects as many as 125 million people worldwide. Current therapeutics for psoriasis include systemic acting immuno-suppressive drugs for which the long-term effects remain a concern. Psoriasis is a cell-mediated disease dependent on T helper (Th) 17 effector cells that are biased by cutaneous DCs. Importantly, the stimuli that induce DCs and keratinocytes to secrete Th polarizing cytokines, particularly in psoriasis, are complex and not completely understood. In this context, ATP is a particularly appealing alarmin that, via P2X7 receptor (P2X7R) signaling, induces NF-κB activation and the IL- 23/IL-17 axis, both of which have been shown to be psoriasis susceptibility pathways. Thus, P2X7R signaling links early inflammatory triggers with psoriasis susceptibility factors. Interestingly, NF-κB also leads to the maintenance of P2X7R expression forming a positive feedback mechanism. Results from our ongoing studies support a currently unappreciated role for P2X7R signaling in psoriasis pathogenesis. Specifically, we provide evidence that in healthy human skin, P2X7R signaling induces innate immunity, stimulates DCs to express IL-1ß, IL-6, IL-23, IL-15, and VEGF, and promotes a Th17 bias. Additionally, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. This increased P2X7R expression in non-lesional skin represents a primary abnormality in the skin of patients with psoriasis, rather than a secondary effect of inflammation. Supported by this theoretical and experimental rationale, we hypothesize that within a genetically susceptible microenvironment cutaneous P2X7R signaling is a mechanism of psoriasis pathogenesis that can be a target for therapeutics. Thus, our goal in this preclinical proposal is to determine the involvement of P2X7R signaling in the development and maintenance of psoriatic lesions, and to elucidate novel P2X7R-dependent pathogenic mechanisms that can be exploited for novel psoriasis therapies. To test our novel and innovative hypothesis we have established the following specific aims: Aim 1 will define the inflammatory pathways induced by cutaneous P2X7R signaling. Aim 2 will establish the involvement of P2X7R signaling in psoriasis pathogenesis within a genetically susceptible microenvironment, and Aim 3 will examine the therapeutic capacity of P2X7R antagonist to diminish psoriatic lesions. The conserved nature of ATP and P2X7R signaling pathways in mice and humans supports the translational value of the studies we propose and provide an opportunity to utilize a unique and innovative approach by combing both human and murine models of psoriasis. At the conclusion of this proposal we will have determined that P2X7R signaling is pathogenic in genetically susceptible psoriatic microenvironments. Our results will lead to an increased scientific knowledge base, the development of a model to further examine P2X7R signaling mechanisms and psoriasis pathogenesis, and proof-of-principle studies for new therapeutic strategies for future proposals.