糖基化终末产物活化角质形成细胞NLRP3炎症小体促进银屑病发病的作用和机制研究

Psoriasis is a common inflammatory skin disease. Metabolic disorder is strongly associated with psoriasis, but the specific role of metabolic disorder in psoriatic inflammation is not clear. Advanced glycation end products (AGEs) are a kind of proinflammatory metabolic end products. The content of AGEs is significantly enhanced in the patients with metabolic syndrome. Recent studies have found that the level of AGEs is elevated in the serum and the lesion of psoriasis patients, indicating that AGEs may participate in the formation of psoriasis. Previously, our research group found that the level of AGEs is enhanced in lesional keratinocytes of psoriasis. Further in vitro studies demonstrated that AGEs facilitated the expressions of the component proteins of NLRP3 inflammasome as well as NEK7 that is a key protein upstream of NLRP3 activation, implicating that AGEs could activate NLRP3 inflammasome in psoriatic keratinocytes. Based on these findings, we hypothesized that AGEs accumulated in the epidermis could activate NLRP3 inflammasome in keratinocytes, promote the production and the secretion of inflammatory factors from keratinoyctes, and thus contribute to the formation of psoriatic inflammation. The current project intends to elucidate the effects of AGEs on the activation of NLRP3 inflammasome in keratinocytes and clarify the role of AGEs in the development of psoriasis. The potential findings of the project will help to create a better understanding on the involvement of metabolic disorder in psoriasis and provide new strategies for the prevention and the treatment of psoriasis.

银屑病是常见的慢性炎症性皮肤病，代谢异常与银屑病发病密切相关，但其具体作用尚不清楚。糖基化终末产物是一种促炎代谢终产物，其含量在代谢综合征患者体内显著增多。最新研究表明，银屑病患者体内糖基化终末产物水平升高，提示其可能参与银屑病发病。我们前期证实，糖基化终末产物在银屑病皮损角质形成细胞中增多，体外实验发现其能够促进角质形成细胞中NLRP3炎症小体组分蛋白及其活化关键分子NEK7的表达，提示糖基化终末产物可能激活银屑病角质形成细胞NLRP3炎症小体。据此，我们提出如下假说：糖基化终末产物在表皮蓄积，通过活化角质形成细胞NLRP3炎症小体，促进角质形成细胞释放炎症因子，参与银屑病炎症反应。本项目拟在分子、细胞、动物及人群水平阐明糖基化终末产物通过活化角质形成细胞NLRP3炎症小体促进银屑病发病的作用机制，预期结果将为认识代谢异常参与银屑病发病的机理及指导银屑病预防与治疗提供新思路。

银屑病是一种常见的慢性炎症性皮肤病，皮肤角质形成细胞固有免疫功能激活从而分泌一系列炎症因子促进T细胞免疫反应是银屑病发病的重要环节，但其分子机制尚不清楚。代谢异常与银屑病发病紧密相关，但其在银屑病发病机制中的具体作用仍未阐明。本研究围绕这些科学问题，以糖基化终末产物为切入点，旨在从分子和细胞水平系统阐明糖基化终末产物激活角质形成细胞固有免疫功能的具体分子机制，在此基础上确证糖基化终末产物促进银屑病炎症反应的重要作用，并在临床银屑病样本中全面鉴定与分析糖基化终末产物与银屑病发生发展的相关性，从而丰富代谢异常参与银屑病发病的机理。围绕上述研究内容，本项目首先明确了银屑病患者体内血清和皮损的糖基化终末产物水平均显著升高，且血清糖基化终末产物水平与银屑病病情严重程度呈正相关。其次，糖基化终末产物可通过增加角蛋白K17表达，诱导细胞周期调控蛋白p27的出核降解，从而促进角质形成细胞的细胞周期进展和增殖。接着，糖基化终末产物可促进角质形成细胞表达和分泌重要的细胞因子IL-36α，并可通过IL-36α增强Th17细胞免疫反应及细胞因子IL-17A的表达。最后，糖基化终末产物促进角质形成细胞增殖和产生IL-36α的双重作用均由STAT1/STAT3信号通路活化介导。通过上述研究，本项目阐明了糖基化终末产物促进角质形成细胞固有免疫功能活化及增殖的效应和分子机制，并明确了其增强Th17细胞免疫反应的重要作用，并验证了STAT1/STAT3信号通路在其中的介导作用，完成了预定的研究目标，为代谢异常与银屑病发病相关的临床现象提供了潜在机制。