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 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 st...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/76744 |
| _version_ | 1798023228097036288 |
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| author | Amy L Seufert James W Hickman Ste K Traxler Rachael M Peterson Trent A Waugh Sydney J Lashley Natalia Shulzhenko Ruth J Napier Brooke A Napier |
| author_facet | Amy L Seufert James W Hickman Ste K Traxler Rachael M Peterson Trent A Waugh Sydney J Lashley Natalia Shulzhenko Ruth J Napier Brooke A Napier |
| author_sort | Amy L Seufert |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T17:42:59Z |
| format | Article |
| id | doaj.art-11ab3fcbf7ef42cc9ecc00140c2d5947 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T17:42:59Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-11ab3fcbf7ef42cc9ecc00140c2d59472022-12-22T04:11:26ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.76744Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infectionAmy L Seufert0https://orcid.org/0000-0001-9777-6793James W Hickman1Ste K Traxler2Rachael M Peterson3Trent A Waugh4Sydney J Lashley5Natalia Shulzhenko6Ruth J Napier7Brooke A Napier8https://orcid.org/0000-0002-6409-4750Department of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesDepartment of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesDepartment of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesDepartment of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesDepartment of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesVA Portland Health Care System, Portland, United StatesDepartment of Biomedical Sciences, Oregon State University, Corvallis, United StatesVA Portland Health Care System, Portland, United States; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesDepartment of Biology and Center for Life in Extreme Environments, Portland State University, Portland, United StatesTrained 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.https://elifesciences.org/articles/76744trained immunityinnate immune memorymacrophagesinflammationpalmitic acidceramide |
| spellingShingle | Amy L Seufert James W Hickman Ste K Traxler Rachael M Peterson Trent A Waugh Sydney J Lashley Natalia Shulzhenko Ruth J Napier Brooke A Napier Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection eLife trained immunity innate immune memory macrophages inflammation palmitic acid ceramide |
| title | Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| title_full | Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| title_fullStr | Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| title_full_unstemmed | Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| title_short | Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| title_sort | enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection |
| topic | trained immunity innate immune memory macrophages inflammation palmitic acid ceramide |
| url | https://elifesciences.org/articles/76744 |
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