Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection
- Portland State University, United States
- VA Portland Health Care System, United States
- 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
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
- 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
- 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)
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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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
Further reading
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- Cell Biology
- Immunology and Inflammation
Cytokine polyfunctionality is a well-established concept in immune cells, especially T cells, and their ability to concurrently produce multiple cytokines has been associated with better immunological disease control and subsequent effectiveness during infection and disease. To date, only little is known about the secretion dynamics of those cells, masked by the widespread deployment of mainly time-integrated endpoint measurement techniques that do not easily differentiate between concurrent and sequential secretion. Here, we employed a single-cell microfluidic platform capable of resolving the secretion dynamics of individual PBMCs. To study the dynamics of poly-cytokine secretion, as well as the dynamics of concurrent and sequential polyfunctionality, we analyzed the response at different time points after ex vivo activation. First, we observed the simultaneous secretion of cytokines over the measurement time for most stimulants in a subpopulation of cells only. Second, polyfunctionality generally decreased with prolonged stimulation times and revealed no correlation with the concentration of secreted cytokines in response to stimulation. However, we observed a general trend towards higher cytokine secretion in polyfunctional cells, with their secretion dynamics being distinctly different from mono-cytokine-secreting cells. This study provided insights into the distinct secretion behavior of heterogenous cell populations after stimulation with well-described agents and such a system could provide a better understanding of various immune dynamics in therapy and disease.
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
