Trained immunity is epigenetic reprogramming that occurs in innate immune cells in response to primary inflammatory stimuli and leads to enhanced inflammation upon secondary challenge with homologous or heterologous stimuli. We find exposure to high-fat diets confers a hyper-inflammatory response to systemic LPS and enhanced mortality, independent of microbiome. Ketogenic diet (KD) does not alter homeostatic inflammation, but enhances the response of immune cells to LPS challenge ex vivo. Lipidomics identified dietary palmitic acid (C16:0; PA) may be acting as a primary inflammatory stimulus in our model. Here we show PA induces a hyper-inflammatory response to LPS challenge in cultured macrophages and in vivo, correlating with increased endotoxemia mortality and enhanced resistance to C. albicans infection in RAG-/- mice. Our study identifies PA is an inducer of trained immunity that leads to a hyper-inflammatory response to secondary heterologous stimuli, and is deleterious during systemic inflammation, but enhances resistance to infection.

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