CD100调控角质形成细胞糖酵解代谢在银屑病发病中的作用及机制研究

Psoriasis is a chronic inflammatory skin disease, the active of keratinocyte (KC) glycolysis, which is closely related to its inflammatory progress, but the causal mechanism is still unclear. The studies have shown that immunoregulatary molecules, CD100 and its receptor of Plexin-B2 were highly expressed in psoriatic lesion. We previously found that CD100/Plexin-B2 significantly promoted KC glycolysis in vitro; meanwhile, lactate, the product of glycolysis could effectively promote KC NLRP3 inflammasome activation and the release of the pro-inflammatory cytokines. Therefore, we put forward the hypothesis that CD100/Plexin-B2 promoted KC glycolysis, which is involved in inflammatory response of psoriasis. We will firstly confirm that glycolysis is implicated in the development of psoriasis in clinical samples and IMQ-induced psoriasis-like mouse model, and then explore the underlying mechanism of CD100 in regulating glycolysis involved in inflammatory response of psoriasis, and finally to verify the effect of CD100 on KC glycolysis and psoriasis inflammatory response in IMQ psoriasis-like dermatitis model. This study will illustrate the specific mechanism of CD100 regulating KC glycolysis on psoriasis inflammatory response, which may help to develop new therapeutic treatments for psoriasis.

银屑病是一种慢性炎症性皮肤病，角质形成细胞（KC）活跃的糖酵解代谢与其炎症进展密切相关，但机制不清。研究表明，免疫调节分子CD100及其受体Plexin-B2在银屑病患者表皮KC中高表达。我们发现，CD100/Plexin-B2促进KC糖酵解代谢，而代谢终产物乳酸可促进NLRP3炎症小体活化和促炎细胞因子的分泌。以上结果提示：银屑病表皮KC高表达的CD100/Plexin-B2促进KC糖酵解代谢终产物乳酸产生，进而促进NLRP3炎症小体活化参与银屑病炎症反应。本项目拟首先在临床样本和银屑病小鼠模型中明确糖酵解代谢与CD100及银屑病发病的关系；进一步在细胞水平阐明CD100调控KC糖酵解代谢参与银屑病炎症的具体机制；最后在小鼠模型中确认干预CD100对KC糖酵解代谢和银屑病样损害发生的影响。旨在揭示KC糖酵解代谢参与银屑病炎症的具体分子机制，为银屑病治疗提供新的策略和关键靶点。

银屑病是一种慢性炎症性皮肤病，角质形成细胞（KC）活跃的糖酵解代谢与其炎症进展密切相关，其机制有待进一步阐明。我们前期收集多例银屑病患者的皮损组织和外周血样本以及构建咪喹莫特诱导的小鼠银屑病样模型，发现CD100及其受体Plexin-B2在银屑病患者皮损表皮和咪喹莫特诱导的小鼠银屑病样模型表达水平显著升高；糖酵解代谢关键限速酶和乳酸水平在银屑病患者和咪喹莫特诱导的小鼠银屑病样模型皮损表皮和血清中显著升高，并且血清中可溶性CD100和乳酸水平与病情严重程度PASI评分呈正相关。单细胞数据库和GSEA数据库结果也显示银屑病皮损表皮糖酵解代谢能力显著增强。在体外细胞水平，利用混合炎症因子刺激人角质形成细胞系模拟银屑病皮损微环境，发现其糖酵解代谢水平显著升高。并且，CD100/Plexin-B2促进KC糖酵解代谢关键酶表达水平升高及葡萄糖消耗、乳酸产生和LDH酶活性增加。机制上，我们发现CD100/Plexin-B2活化MAPK信号促进KC糖酵解代谢；进一步验证发现糖酵解代谢的终产物乳酸产生促进KC NLRP3炎症小体活化及炎症因子表达。在体动物水平，我们研究发现与野生型小鼠相比，CD100敲除小鼠γδTCR和Gr1等炎症分子表达水平升高；同时，IL-23、IL-22、IL-17和IL-1β等炎症细胞因子表达水平明显增强；并且，CD100敲除小鼠皮损表皮糖酵解代谢能力和糖酵解代谢关键酶表达水平明显降低。通过以上结果证实银屑病皮损表皮高表达的CD100/Plexin-B2，通过活化MAPK信号促进KC糖酵解代谢终产物乳酸产生，乳酸积累进一步促进KC NLRP3炎症小体活化及炎症因子分泌，参与银屑病免疫炎症反应。本项目顺利实施探索了CD100调控KC糖酵解代谢参与银屑病炎症的具体机制，为以CD100和角质形成细胞糖酵解代谢为靶标治疗银屑病提供了理论基础和临床依据。

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