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

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Abstract Obesity and a high-fat diet are known risk factors for incident psoriasis that can interfere with the efficiency of existing psoriasis treatments. The development of psoriasis profoundly depends on the cytokine IL-23 produced by dendritic cells (DCs) and macrophages and inducing psoriatic skin inflammation. We and others have previously shown that diets rich in fatty acids exacerbate psoriasis by enhancing inflammatory IL-23 signaling in the skin. However, molecular mechanisms that link excessive dietary fatty acids to increased IL-23 production by DCs are not entirely understood. In a mouse model of psoriasis, we have recently shown that IL-23-producing DCs mediate the harmful effect of a diet rich in fat to skin inflammation. Excessive dietary palmitic acid (PA) metabolically reprogrammed DCs to enhance the unfolded protein response (UPR) in the endoplasmic reticulum, which led to sustained IL-23 expression. We found that the deficiency of the UPR-activated transcription factor XBP1 in DCs diminishes IL- 23 expression and protects mice from the high-fat diet feeding-mediated exacerbation of psoriasis. Thus, it is critical to identify the molecular link between the metabolic reprogramming of DCs by PA and the UPR-dependent inflammation to understand how obesity exacerbates 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 the respiratory activity of mitochondria. Accordingly, the central premise of this project is that understanding how the Malate-Aspartate shuttle connects a high fatty acid environment to a specific inflammatory response in dendritic cells will open new avenues for therapeutic approaches to treat inflammatory diseases in obesity. In this project, we will use pharmacological and genetic models of psoriasis to identify and validate metabolic, signaling, and immune components that regulate IL-23 production in DCs in the context of obesity. Specific Aim 1 is focused on understanding how PA reprograms metabolism and mitochondrial function in DCs to increase Malate-Aspartate shuttle activity. Specific Aim 2 is focused on the characterization of molecular mechanisms that link the Malate- Aspartate shuttle to the UPR as the regulator of DC inflammatory functions in psoriasis, with increased IL-23 production as a hallmark.