Palmitic acid reprograms inflammatory responses to microbial ligands in macrophages, and mediates innate immune memory in vivo.

Abstract

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.