Brooke Ann Napier
Date of Award
Bachelor of Science (B.S.) in Biology and University Honors
Palmitic acid, Macrophages, glycolysis, Glycolytic genes, Pro-inflammatory cytokines, Metabolism, Sepsis, Inflammation, SFA, Trained immunity
Trained immunity is long-term innate immune memory induced by a primary stimulus, which leads to hyper-inflammation upon secondary stimulation with a homologous or heterologous ligand. Trained immunity is mediated by epigenetic and metabolic reprogramming of the target cell and leads to modification of gene expression and cellular function. Classically, trained immunity is initiated by β-glucans, an inflammatory molecule found on the exterior of fungal species. Interestingly, our lab has recently described that dietary fatty acids can initiate trained immunity, working through similar pathways as β-glucans. Specifically, our data show that a pre-treatment with a specific dietary saturated fatty acid (SFA), palmitic acid (PA), initiates trained immunity in macrophages, leading to a hyper-inflammatory response to a secondary challenge with numerous microbial ligands. Macrophages are tissue-specific innate immune cells that play a key role in orchestrating inflammatory diseases and infection. Though we have reported PA-dependent trained immunity leads to a hyper-inflammatory response, it is unknown if PA induces metabolic changes associated with induction of trained immunity. Specifically, enhanced glycolysis occurs during the trained immune response. Thus, the goal of this study is to determine if PA enhances glycolysis, like classical stimulants of trained immunity, during enhanced inflammation upon secondary stimulation with LPS. We aim to quantify the expression of three key glycolytic genes within mouse macrophages with PA-induced trained immunity: 1) glut1, which allows glucose to enter the cell, and 2) hk2 and 3) pfkp, which encode for two rate-limiting enzymes in glycolysis. We hypothesized that PA induces glycolysis during trained immunity in macrophages. We found that after 24h of treatment with PA followed by a secondary heterologous stimulus, PA-induced expression of glut1, but not hk2 or pfkp. Additionally, if we treated macrophages with PA for 24h, rested it for 24h, and then added a secondary stimulus, there was no longer a significant increase in expression of hk2. Our results indicate that PA may enhance glycolysis during the trained immune response, however, if the macrophage is rested for 24h after exposure to PA, it no longer induces a glycolytic response. These data highlight the dynamic glycolytic response of the macrophage during PA-dependent trained immunity. The capacity for PA to directly impact innate immune metabolism associated with inflammatory pathways may inform dietary interventions and treatments for patients with acute or chronic inflammatory diseases.
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Aqaei, Khaleda A., "Understanding the Effect of Dietary Palmitic Acid on Glycolysis During Innate Immune Memory in Macrophages" (2021). University Honors Theses. Paper 1154.
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