Trained immunity is an innate immune memory response that is induced by primary microbial or sterile stimuli that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Nutritional components, such as dietary fatty acids, can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli in the context of innate immune memory. Here we find mice fed a diet enriched exclusively in saturated fatty acids (SFAs; ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and glycemic modulation. We find KD mediates the composition of the hematopoietic stem cell (HSC) compartment, and macrophages derived from the bone marrow of mice fed KD do not have altered baseline inflammation, but enhanced responses to a secondary inflammatory challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in KD-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA alone reprograms macrophages to induce a hyper-inflammatory response to secondary challenge with LPS. This response was found to be dependent on the synthesis of ceramide, and reversible when treated with a ceramide synthase inhibitor. In vivo, we found systemic PA confers enhanced inflammation and mortality during an acute inflammatory response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. While PA-treatment is harmful for endotoxemia outcome, we find PA exposure enhanced clearance of Candida albicans in Rag1-/- mice. Further, we show that oleic acid (OA), a mono-unsaturated FA that depletes intracellular ceramide, reverses the PA-induced hyper-inflammatory response shown in macrophages treated with LPS, and reduces severity and mortality of LPS endotoxin stimulation, highlighting the plasticity of SFA-dependent enhanced endotoxemia severity in vivo. These are the first data to implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory that is detrimental during an acute inflammatory response, but beneficial for clearance of pathogens.
Dietary saturated fatty acids (SFAs) modulate circulating lipids in mice and humans, which can alter the inflammatory capacity of innate immune cells. The most common SFA in human serum, palmitic acid (PA), is enriched in Western diets, and while it is known to induce an inflammatory response in macrophages, the impact of PA on responses to pathogenic stimuli is unknown. We developed an in vitro model to determine the impact of PA on the macrophage response to lipopolysaccharide (LPS). We find that bone marrow-derived macrophages (BMDMs) exposed to PA for 12–24 hours exhibit significantly enhanced TNF, IL-6 and IL-1β secretion following LPS exposure. BMDMs treated simultaneously with PA and the unsaturated fatty acid oleic acid (OA) show a reversal of this PA-induced hyper-inflammatory response to LPS, suggesting that OA negatively regulates the memory-like feature of PA. While monocytes and splenocytes from mice fed a PA-enriched diet exhibit unaltered basal inflammation, ex vivo LPS treatment leads to significantly enhanced pro-inflammatory cytokine expression. Mice exposed to PA for 9 days, followed by 7 days without PA, exhibit increased LPS-induced endotoxemia severity and mortality, and enhanced mRNA expression of tnf, il-6, and il-1β in blood. Rag−/− mice exposed to PA for 12-hours showed significantly reduced kidney fungal burden after Candida albicans infection. We hypothesize that PA induces a long-lasting innate immune memory program in macrophages, and reprograms their response to subsequent inflammatory challenge via metabolic and epigenetic alterations. Our findings are the first to suggest dietary PA regulates innate immune memory and is detrimental in an acute septic response, yet beneficial for pathogen clearance. Supported by National Institute of General Medical Sciences (NIGMS) 525 grant 5R35GM133804-02 to B.A.N.
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