Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection
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.
All data generated or analyzed during this study are included in the manuscript and supporting file.
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- Brooke A Napier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#IP00002661 & IP00001903) of Oregon Health & Sciences University and Oregon State University (#5091). All animal experiments were approved by the Oregon Health and Sciences University (OHSU) Department of Comparative Medicine or Oregon State University (OSU) Animal Program Office and were overseen by the Institutional Care and Use Committee (IACUC).
- Jos W van der Meer, Radboud University Medical Centre, Netherlands
- Preprint posted: June 16, 2021 (view preprint)
- Received: January 4, 2022
- Accepted: October 19, 2022
- Accepted Manuscript published: October 20, 2022 (version 1)
- Version of Record published: November 8, 2022 (version 2)
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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