Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.

Autor:	Seufert AL; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States., Hickman JW; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States., Traxler SK; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States., Peterson RM; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States., Waugh TA; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States., Lashley SJ; VA Portland Health Care System, Portland, United States., Shulzhenko N; Department of Biomedical Sciences, Oregon State University, Corvallis, United States., Napier RJ; VA Portland Health Care System, Portland, United States.; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States., Napier BA; Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Oct 20; Vol. 11. Date of Electronic Publication: 2022 Oct 20.
DOI:	10.7554/eLife.76744
Abstrakt:	Trained immunity is an innate immune memory response that is induced by a primary inflammatory stimulus that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Dietary fatty acids can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli to induce trained immunity. Here we find mice fed a diet enriched exclusively in saturated fatty acids (ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and hyperglycemia. We find KD alters the composition of the hematopoietic stem cell compartment and enhances the response of bone marrow macrophages, monocytes, and splenocytes to secondary LPS 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 induces a hyper-inflammatory response to LPS in macrophages, and this was dependent on the synthesis of ceramide. In vivo, we found systemic PA confers enhanced inflammation and mortality in response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. Conversely, we find PA exposure enhanced clearance of Candida albicans in Rag1 -/- mice. Lastly, we show that oleic acid, which depletes intracellular ceramide, reverses PA-induced hyper-inflammation in macrophages and enhanced mortality in response to LPS . These implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory and highlight the plasticity of this innate immune reprogramming by dietary constituents. Competing Interests: AS, JH, ST, RP, TW, SL, NS, RN, BN No competing interests declared
Databáze:	MEDLINE
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