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

  1. Amy L Seufert
  2. James W Hickman
  3. Ste K Traxler
  4. Rachael M Peterson
  5. Trent A Waugh
  6. Sydney J Lashley
  7. Natalia Shulzhenko
  8. Ruth J Napier
  9. Brooke A Napier  Is a corresponding author
  1. Portland State University, United States
  2. VA Portland Health Care System, United States
  3. Oregon State University, United States

Abstract

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file.

Article and author information

Author details

  1. Amy L Seufert

    Department of Biology, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. James W Hickman

    Department of Biology, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ste K Traxler

    Department of Biology, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rachael M Peterson

    Department of Biology, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Trent A Waugh

    Department of Biology, Portland State University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sydney J Lashley

    VA Portland Health Care System, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Natalia Shulzhenko

    Department of 9Biomedical Sciences, Oregon State University, Corvallis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ruth J Napier

    VA Portland Health Care System, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Brooke A Napier

    Department of Biology, Portland State University, Portland, United States
    For correspondence
    brnapier@pdx.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6409-4750

Funding

NIGMS/NIH (R35GM133804)

  • Brooke A Napier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jos W van der Meer, Radboud University Medical Centre, Netherlands

Ethics

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).

Version history

  1. Preprint posted: June 16, 2021 (view preprint)
  2. Received: January 4, 2022
  3. Accepted: October 19, 2022
  4. Accepted Manuscript published: October 20, 2022 (version 1)
  5. Version of Record published: November 8, 2022 (version 2)

Copyright

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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  1. Amy L Seufert
  2. James W Hickman
  3. Ste K Traxler
  4. Rachael M Peterson
  5. Trent A Waugh
  6. Sydney J Lashley
  7. Natalia Shulzhenko
  8. Ruth J Napier
  9. Brooke A Napier
(2022)
Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection
eLife 11:e76744.
https://doi.org/10.7554/eLife.76744

Share this article

https://doi.org/10.7554/eLife.76744

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