健脾养血解毒方通过糖酵解代谢重编程正向调节银屑病血燥证Treg细胞迁移的机制研究

Blood dryness syndrome is the main type of chronic skin lesions in psoriasis vulgaris. Spleen deficiency with dampness and toxin accumulation and blood dryness with no nutrition in skin are the important pathogenesis of psoriasis vulgaris with blood dryness syndrome.The chronic course of psoriasis is closely related to the weakened migration ability of Treg cells.Recent studies have shown that the migration function of Treg is not provided with energy by lipid oxidation, but regulated by glycolysis, promoting migration through the combination of glucose kinase and actin.In the early stage, our group found that the clinically effective prescription for the blood dryness syndrome is Jianpiyangxuejiedu decoction, significantly improve the psoriasis skin lesions, increase the proportion of skin Treg, and enhance its migration.On this basis, a hypothesis was proposed that Jianpiyangxuejiedu decoction might induce the reprogramming of glycolysis metabolism through Rictor/mTORC2 pathway, enhance the migration function of Treg, and thereby inhibit the continuous activation of the immune response.In this study, Treg glycolysis were used as the entry point to determine the Treg migration ability in peripheral blood of patients with psoriasis with psoriasis syndrome before and after treatment, so as to determine the correlation between Treg migration disorder and disease severity.Taking spleen deficiency combined with psoriasis dermatitis and Treg cells isolated in vitro as models, the mechanism of action of spleen-nourishing blood-detoxifying recipe on mTORC2 pathway mediated Treg glycolysis reprogramming to promote migration will studied, and the therapeutic target of this recipe on psoriasis blood dryness syndrome will clarified.

血燥证是寻常型银屑病慢性皮损的主要证型，脾虚湿毒内蕴、血燥肌肤失养是其重要病机。银屑病慢性病程与Treg细胞迁移能力减弱有密切关系。最新研究表明Treg迁移功能不是由脂质氧化提供能量，而是受糖酵解代谢重编程调控，通过葡萄糖激酶与肌动蛋白结合促迁移。课题组前期发现血燥证临床有效方剂健脾养血解毒方，显著改善银屑病皮损、上调皮肤Treg比例、增强其迁移。在此基础上提出假说：健脾养血解毒方可能通过Rictor/mTORC2通路诱导糖酵解代谢的重编程，增强Treg迁移功能，从而抑制免疫反应持续激活。本研究拟以Treg糖酵解代谢为切入点，通过检测银屑病血燥证患者治疗前后外周血Treg迁移能力，明确Treg迁移障碍与疾病严重程度的相关性；以脾虚复合银屑病样皮损和体外分离Treg细胞为模型，研究健脾养血解毒方对mTORC2通路介导的Treg糖酵解重编程促迁移的作用机制，阐明该方治疗银屑病血燥证的作用靶点。

在银屑病慢性病程的皮损中，具有免疫抑制功能的Treg细胞存在迁移障碍，无法趋化至炎症反应中心，致使皮损部位免疫激活状态持续存在，是银屑病炎症皮损迁延难愈的重要机制之一。银屑病血燥证是临床慢性皮损的重点难治证型。健脾养血解毒方为银屑病血燥证的有效方剂，临床疗效显著，对健脾养血解毒方治疗环节及作用靶点的阐述有利于对疾病的认识及对临床治疗药物的进一步开发和推广。本研究通过临床与基础研究相结合，从Treg细胞向皮肤的迁移功能和能量代谢重编程入手，以健脾养血解毒方及其主要靶器官倾向性药物成分进行干预，阐明健脾养血解毒法治疗银屑病血燥证的作用机制，丰富健脾养血解毒方的现代分子免疫机制。经过对健脾养血解毒方在银屑病状态下入血及入皮肤靶器官的药效物质分析，明确健脾养血解毒方治疗银屑病血燥证的潜在活性成分。通过建立并鉴定咪喹莫特复合高脂饲养联合大黄灌胃诱导的银屑病血燥证样小鼠模型，明确脾虚血燥因素增强机体对炎症激活状态的高响应水平及其作用环节，阐明银屑病血燥证作为慢性病程主要证型的免疫学基础。在此基础上，检测健脾养血解毒方及其主要潜在药物成分对银屑病血燥证免疫反应中炎性细胞及炎性因子的表达影响，明确其对Terg细胞在机体不同组织中表达和Treg细胞的迁移表型的影响，阐明药物对Treg细胞迁移功能及抑炎功能的调节机制及作用通路。体外分离银屑病血燥证患者外周血原代Treg细胞及小鼠原代Treg细胞，检测药物对Treg细胞的迁移表型及糖酵解代谢的重编程的干预，明确药物对Treg细胞在迁移状态下糖酵解代谢重编程的作用靶点，为健脾养血解毒法治疗银屑病血燥证的临床应用提供有力的基础研究证据。