Dietary palmitic acid induces innate immune memory via ceramide production that enhances severity of acute septic shock and clearance of infection

Abstract

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.

Weight cycling induces innate immune memory in adipose tissue macrophages

“…Priming with palmitic acid increases the response to many innate stimuli, including TLR2, TLR4, and dectin-1 agonists. Napier and colleagues have shown that other models of palmitate treatment can augment macrophage inflammation in culture and induce an innate memory-like effect 39 . Moreover, her group showed that dietary palmitate can augment the inflammatory response to endotoxemia and improve the clearance of Candida albicans in vivo.…”

“…Palmitic acid was chosen as our initial stimulus because it is the most common saturated fatty acid in the human body, is elevated in individuals with obesity due to lipolysis, and it activates TLR4, a receptor that can promote innate immune memory 36 . Additionally, palmitate has been shown to elicit an obese-like adipose macrophage phenotype in bone marrow derived macrophages (BMDM) and priming in other models [37][38][39] . Following 24-hour activation and a 6-day washout, palmitic acid priming increased maximal extracellular acidification rate (ECAR), a proxy for glycolysis, and appeared to increase maximal oxygen consumption rate (OCR), a proxy for oxidative phosphorylation, although this measure was not significant (Figure 2B&C).…”

Weight cycling induces innate immune memory in adipose tissue macrophages

“…Palmitic acid was chosen as our initial stimulus because it is the most common saturated fatty acid in the human body, is elevated in individuals with obesity due to lipolysis, and it activates TLR4, a receptor that can promote innate immune memory (37). Additionally, palmitate has been shown to elicit an obese-like adipose macrophage phenotype in bone marrow derived macrophages (BMDM) and priming in other models (38)(39)(40). Following 24-hour activation and a 6-day washout, palmitic acid priming increased maximal extracellular acidification rate (ECAR), a proxy for glycolysis, and modestly increased maximal oxygen consumption rate (OCR), a proxy for oxidative phosphorylation, although this measure was not significant (Figures 2B, C).…”