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

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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.