P2X7R Signaling in Psoriasis Pathogenesis

描述（由申请人提供）：牛皮癣是一种皮肤自身免疫性疾病，影响全球多达1.25亿人。目前银屑病的治疗方法包括全身性免疫抑制药物，其长期效果仍然值得关注。银屑病是一种细胞介导的疾病，依赖于T辅助（Th） 17效应细胞，其偏向于皮肤dc。重要的是，诱导dc和角质形成细胞分泌极化细胞因子的刺激，特别是在牛皮癣中，是复杂的，尚未完全了解。在这种情况下，ATP是一个特别吸引人的警示因子，它通过P2X7受体（P2X7R）信号传导，诱导NF-κ b激活和IL- 23/IL-17轴，这两者都被证明是银屑病的易感性途径。因此，P2X7R信号将早期炎症触发因素与银屑病易感性因素联系起来。有趣的是，NF-κB也导致P2X7R表达的维持，形成正反馈机制。我们正在进行的研究结果支持P2X7R信号在银屑病发病机制中的作用。具体来说，我们提供的证据表明，在健康的人类皮肤中，P2X7R信号可诱导先天免疫，刺激dc表达IL-1ß、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的P2X7R表达增加。P2X7R在非病变皮肤中的表达增加代表牛皮癣患者皮肤的原发性异常，而不是炎症的继发效应。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信号是银屑病发病的一种机制，可以成为治疗的靶点。因此，我们的临床前研究目标是确定P2X7R信号在银屑病病变发展和维持中的作用，并阐明新的P2X7R依赖的致病机制，从而开发新的银屑病治疗方法。为了验证我们的新颖和创新的假设，我们建立了以下具体目标：目的1将定义皮肤P2X7R信号诱导的炎症途径。目的2将在遗传易感的微环境中确定P2X7R信号在银屑病发病中的作用，目的3将研究P2X7R拮抗剂减少银屑病病变的治疗能力。ATP和P2X7R信号通路在小鼠和人类中的保守性支持了我们提出的研究的转化价值，并提供了利用独特和创新的方法结合人类和小鼠牛皮癣模型的机会。在本文的结论中，我们将确定P2X7R信号在遗传易感的银屑病微环境中是致病的。我们的研究结果将增加科学知识基础，进一步研究P2X7R信号机制和牛皮癣发病机制的模型，并为未来的新治疗策略提供原理验证研究。

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.