Differential regulation of lipopolysaccharide-induced IL-1β and TNF-α production in macrophages by palmitate via modulating TLR4 downstream signaling

Fang, Chunyun; Wang, Lixia; Qiao, Jingting; Chang, Lei; He, Qing; Zhang, Xiaona; Liu, Ming

doi:10.1016/j.intimp.2021.108456

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…TNF, IL-6, and IL-1β) from splenocytes and myeloid-derived innate immune cells ( Lewis et al, 2016 ; Wang et al, 2016 ; Radzyukevich et al, 2021 ; Zhang et al, 2012 ). Additionally, pre-treatment of myeloid-derived cells with dietary SFAs has been shown to enhance inflammatory pathways in response to microbial ligands ( Schwartz et al, 2010 ; Fang et al, 2022 ). Considering this, we hypothesized that exposure to enriched systemic dietary SFAs in WD- and KD-fed mice would enhance the inflammatory response to systemic LPS during the acute inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

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

Seufert

Hickman

Traxler

et al. 2022

eLife

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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.

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Section: Resultsmentioning

confidence: 99%

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

Seufert

Hickman

Traxler

et al. 2022

eLife

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“…Lastly, as mentioned previously, canonical-trained immunity induced by β-glucans or BCG vaccine leads to long-term metabolic and functional reprogramming of myeloid cells, and relies on epigenetic alterations for sustained inflammatory capacity. Remarkably, PA-induced memory was [12,17,35,37] Role of mitochondria and MAPK signaling PA pre-treatment + LPS (in vivo)…”

Section: Exogenous Pa and Trained Immunitymentioning

confidence: 99%

“…It was recently shown that immortalized human and mouse macrophage cell lines that were pre-treated with exogenous PA exhibited enhanced LPS-induced TNF secretion [ 37 ] . Schwartz et al showed, in THP-1 monocytes, that the hyper-inflammatory response to LPS following PA-pre-treatment was dependent on ceramide-mediated activation of protein kinase C and mitogen-activated protein kinase signaling pathways [ 35 ] .…”

Section: Exogenous Pa and Trained Immunitymentioning

confidence: 99%

“…Schwartz et al showed, in THP-1 monocytes, that the hyper-inflammatory response to LPS following PA-pre-treatment was dependent on ceramide-mediated activation of protein kinase C and mitogen-activated protein kinase signaling pathways [ 35 ] . While the mechanism for augmented TNF secretion was not defined by Fang et al, the hyper-inflammatory effect of PA-pre-treatment was associated with enhanced phosphorylation of p38 and JNK, and enhanced expression of carnitine palmitoyltransferase1A, an enzymatic shuttle on the outer membrane of mitochondria that facilitates uptake of activated fatty acids into the mitochondrial matrix for β-oxidation [ 37 ] . These data suggest that mitochondrial metabolism plays an important role in the hyper-inflammatory impact of PA-pre-treatment and subsequent challenge with LPS in macrophages [ 35 , 37 ] .…”

Section: Exogenous Pa and Trained Immunitymentioning

confidence: 99%

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A new frontier for fat: dietary palmitic acid induces innate immune memory

Seufert

Napier

2023

Immunometabolism

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Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.

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“…Diets enriched in SFAs induce a hyper-inflammatory response to LPS and increased immunoparalysis LPS-induced acute septic shock mortality results exclusively from a systemic inflammatory response, characterized by an acute increase in circulating inflammatory cytokine levels (ex: TNF, IL-6, and IL-1β) from splenocytes and myeloid derived innate immune cells (24)(25)(26)(27). Additionally, pre-treatment of myeloid-derived cells with dietary SFAs has been shown to enhance inflammatory pathways in response to microbial ligands (28,29). Considering this, we hypothesized that exposure to enriched systemic dietary SFAs in WD-and KD-fed mice would enhance the inflammatory response to systemic LPS during the acute septic response.…”

Section: Introductionmentioning

confidence: 99%

Dietary palmitic acid induces innate immune memory via ceramide production that enhances severity of acute septic shock and clearance of infection

et al. 2021

Preprint

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Trained immunity is epigenetic reprogramming that occurs in innate immune cells in response to primary inflammatory stimuli and leads to enhanced inflammation upon secondary challenge with homologous or heterologous stimuli. We find exposure to high-fat diets confers a hyper-inflammatory response to systemic LPS and enhanced mortality, independent of microbiome. Ketogenic diet (KD) does not alter homeostatic inflammation, but enhances the response of immune cells to LPS challenge ex vivo. Lipidomics identified dietary palmitic acid (C16:0; PA) may be acting as a primary inflammatory stimulus in our model. Here we show PA induces a hyper-inflammatory response to LPS challenge in cultured macrophages and in vivo, correlating with increased endotoxemia mortality and enhanced resistance to C. albicans infection in RAG-/- mice. Our study identifies PA is an inducer of trained immunity that leads to a hyper-inflammatory response to secondary heterologous stimuli, and is deleterious during systemic inflammation, but enhances resistance to infection.

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Differential regulation of lipopolysaccharide-induced IL-1β and TNF-α production in macrophages by palmitate via modulating TLR4 downstream signaling

Cited by 8 publications

References 35 publications

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

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

A new frontier for fat: dietary palmitic acid induces innate immune memory

Dietary palmitic acid induces innate immune memory via ceramide production that enhances severity of acute septic shock and clearance of infection

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