The Malate-Aspartate shuttle links dietary fatty acids to inflammatory responses in dendritic cells

摘要 肥胖和西式饮食是银屑病发病的已知危险因素，它们加剧了现有的银屑病 银屑病。银屑病的发展依赖于皮肤和淋巴中产生的细胞因子IL-23 树突状细胞(DC)和巨噬细胞形成结节。越来越多的证据表明，富含脂肪的饮食 酸通过促进皮肤炎症途径，包括增加IL-23，加重银屑病 制作。然而，将饮食脂肪酸与IL-23产生联系起来的分子机制并不是 完全理解。 我们最近已经证明，在牛皮癣的小鼠模型中，产生IL-23的树突状细胞介导有害的 高脂肪饮食对皮肤炎症的影响。这是由于DC的新陈代谢重新编程 饮食中的棕榈酸(PA)，这导致了增强的未折叠蛋白反应(UPR) 内质网和IL-23表达增加。我们已经证明了 树突状细胞中UPR激活的转录因子XBP1降低IL-23表达并保护小鼠 由HFD喂养介导的牛皮癣加重。因此，鉴定分子是至关重要的。 树突状细胞代谢重编程与UPR依赖炎症之间的联系 肥胖和加重的牛皮癣之间的相互作用。我们的初步结果表明，PA诱导 线粒体应激，并通过激活苹果酸-β-内酯酶增强UPR和IL-23的表达 天冬氨酸穿梭(MAS)，一种连接糖酵解和呼吸活动的中枢代谢途径 线粒体。因此，这个项目的主要前提是了解苹果如何- 天冬氨酸穿梭将高脂肪酸环境与特定的炎症反应联系起来 将为治疗肥胖症的炎症性疾病开辟新的途径。在……里面 在这个项目中，我们将识别和验证调节代谢、信号和免疫的成分 肥胖患者树突状细胞产生IL-23的研究具体目标1侧重于了解PA如何重新编程 树突状细胞的代谢和线粒体功能，以增加苹果酸-天冬氨酸穿梭活性。特定的 目标2的重点是描述将苹果酸-天冬氨酸穿梭连接到 银屑病患者树突状细胞的UPR和炎症功能，以IL-23表达增加为标志。

Abstract Obesity and Western diet are known risk factors for incident psoriasis, and they aggravate existing psoriasis. The development of psoriasis depends on the cytokine IL-23 produced in the skin and lymph nodes by dendritic cells (DCs) and macrophages. There is mounting evidence that diets rich in fatty acids exacerbate psoriasis by enhancing inflammatory pathways in the skin, including increased IL-23 production. However, molecular mechanisms that link dietary fatty acids to IL-23 production are not completely understood. We have recently shown that, in a mouse model of psoriasis, IL-23-producing DCs mediate the harmful effect of a diet rich in fat to skin inflammation. This was due to the metabolic reprogramming of DCs by dietary palmitic acid (PA), which resulted in enhanced unfolded protein response (UPR) in the endoplasmic reticulum and increased IL-23 expression. We have demonstrated that the deficiency of the UPR-activated transcription factor XBP1 in DCs diminishes IL-23 expression and protects mice from the HFD feeding-mediated exacerbation of psoriasis. Thus, it is critical to identify the molecular link between the metabolic reprogramming of DCs and the UPR-dependent inflammation to dissect interplay between obesity and exacerbated psoriasis. Our preliminary results indicate that PA induces mitochondrial stress and enhances the UPR and IL-23 expression via the activation of the Malate- Aspartate shuttle (MAS), a central metabolic pathway connecting glycolysis with respiratory activity of mitochondria. Accordingly, the major premise of this project is that understanding how the Malate- Aspartate shuttle connects a high fatty acid environment to a specific inflammatory response will open new avenues for therapeutic approaches to treat inflammatory diseases in obesity. In this project, we will identify and validate metabolic, signaling, and immune components that regulate IL-23 production in DCs in obesity. Specific Aim 1 is focused on understanding how PA reprograms metabolism of DCs and mitochondrial function to increase Malate-Aspartate shuttle activity. Specific Aim 2 is focused on characterization of molecular mechanisms that link the Malate-Aspartate shuttle to the UPR and inflammatory function of DCs, with increased IL-23 expression as a hallmark, in psoriasis.