乳酸对IL-23/IL-17轴活化和银屑病发病的机制研究

The pathogenesis of psoriasis remains unclear till now. Currently psoriasis is regarded as a chronic recurrent inflammatory disease caused by abnormal immune response process. In recent years, our group focused on the metabolomics and related studies of psoriasis and reported for the first time that glycolytic activity was significantly increased as revealed by high lactic acid levels in psoriasis patients, as commented in the editorial published in the British Journal of Dermatology (BJD). Our hypothesis is that lactic acid could be a potential link between metabolomics and immunology of psoriasis providing that the IL-23/IL-17 axis related immune regulation is affected by lactic acid. Metabolic disorders are closely related to immune disorders, which may cause or promote the occurrence and development of psoriasis. In order to further explore the relationship between lactic acid and psoriasis, the main research contents of this project are: (1) Quantification of lactic acid and related metabolites in human psoriatic skin and healthy skin by using the technique of target metabolomics; (2) Study on the activation mechanism of lactic acid on IL-23/IL-17 axis in psoriasis by in vitro stimulation of APC cells and T cells; (3) Validation the effect of lactic acid on the pathogenesis of psoriasis by constructing animal model of psoriasis. This study will provide clues for the occurrence and development of psoriasis, and give evidence for revealing the pathogenesis of psoriasis.

目前认为银屑病是一由免疫应答过程异常引发的慢性复发性炎症性疾病，发病机制未明。课题组近年来开展银屑病代谢组学及相关研究，首次报道了银屑病患者血清乳酸水平呈显著增加。British Journal of Dermatology为此发表述评，指出我们的研究提示了乳酸是银屑病发生发展中应该引起重视的必要环节。我们推测乳酸对IL-23/IL-17轴相关免疫调节的影响很可能是联系代谢组学与免疫学的桥梁；代谢紊乱与免疫紊乱密切相关，由此引起或促进银屑病发生发展。因此，本项目主要研究内容是（1）应用靶标代谢组学技术量化人银屑病皮损与正常皮肤乳酸及相关代谢物的差异（2）通过体外乳酸刺激银屑病相关抗原递呈细胞（APC）和效应T细胞，研究乳酸对银屑病中IL-23/IL-17轴的活化机制（3）通过构建银屑病鼠模型，验证乳酸对银屑病发病的影响。本研究将为银屑病的发生发展提供线索，为揭示银屑病的发病机制提供依据。

银屑病（Ps）作为一种慢性皮肤炎症，在全球范围内约有1.25亿人受其影响。随着IL-17A以及Th-1和Th-17细胞被发现进一步巩固了对 Ps “细胞因子网络” 的认知。Ps与心血管疾病（CVD）的相关性最早在19世纪90年代被关注。随后许多研究报道了Ps患者患有更高的CVD风险。CVD的传统致病因素以及常见的慢性炎症可以部分的解释Ps患者患有更高CVD的风险。然而作为一种伴随一生的免疫性疾病，尽管其发病机制得到了深入研究，但目前仍然没有根治手段，对Ps的发病机制研究仍具有意义。.本课题，以Ps乳酸代谢异常为切入点，重点研究乳酸及其体内代谢异常对IL-23/IL-17轴的影响，特别是乳酸堆积引起的代谢重编程对银屑病中 IL-23/IL-12 的差异性调控作用。通过建立的两种分析方法，实现了小鼠皮肤和人体血浆中TCA cycle代谢物和氨基酸代谢物含量的检测，进一步展开了相关的代谢组学研究结果表明无论是小鼠皮肤中或人血浆中，Ps组与正常组之间，TCA cycle代谢物和氨基酸含量都有明显差异。.本研究同时探讨了Ps患者相对于健康人体内脂质代谢变化以及接受IL-17A单抗治疗前后的变化。结果发现相对于健康人，Ps患者血浆中的脂质代谢处于异常状态，其中变化最为显着的是异常上调的溶血磷脂。经过 IL-17A mAb 的治疗后Ps患者体内的异常的脂质代谢趋向健康人。随后又进行了拓展研究，对有无患有CVD的Ps患者的血清进行靶标代谢组学研究。结果显示，相比于无CVD的Ps患者，有CVD的Ps患者的体内的脂质代谢更为异常。而 IL-17A mAb 能够改善患有CVD的Ps患者的脂质代谢，从而潜在的降低其患有CVD的风险。.本课题重点探讨Ps患者体内的代谢物重编程变化，进一步拓展研究了这些代谢重编程对Ps患者患有CVD共病的风险的影响，为Ps的治疗、复发以及共病机制研究提供一定的研究基础。