Title

Understanding the Metabolic Regulation of Trained Immunity by Palmitic Acid

Date

11-8-2021 1:20 PM

Abstract

Sepsis is an inflammatory disease that occurs when the body’s response to an infection becomes dysregulated, and infection-fighting processes of the body damage tissues via inflammation, resulting in organ failure and death. Currently, the role for diet in regulating sepsis susceptibility and severity is not fully understood. The Western Diet (WD), the most prevalent diet worldwide, is high in saturated fatty acids (SFAs) and sucrose, and low in fiber. Previously, we have used a lipopolysaccharide (LPS)-induced sepsis mouse model to show that mice fed a Western Diet (WD) or a diet enriched only in SFAs (Ketogenic Diet; KD), experience increased systemic inflammatory disease severity and mortality, compared to mice fed a low-SFA diet. It is unclear how dietary SFAs regulate inflammation during sepsis, however many SFAs have been shown to induce inflammation in monocytes and macrophages, key cell types that regulate inflammation during sepsis. Our preliminary data show that a pre-treatment with a specific dietary SFA, palmitic acid (PA), plays a role in amplifying the inflammatory response of monocytes and macrophages to a secondary challenge with numerous microbial ligands. This PA-induced hyper-inflammation resembles a well-known phenomenon called trained immunity. Trained immunity is a long-term immunological memory induced by a primary stimulus, which leads to hyper-inflammation upon secondary stimulation with a homologous or heterologous ligand. It is mediated by epigenetic and metabolic reprogramming that allows for modification of gene expression and cellular function. It is unknown if PA induces similar metabolic changes required for the induction of trained immunity. The goal of this study is to determine the metabolic pathways within macrophages that are perturbed by PA, and lead to enhanced inflammation upon secondary stimulation with LPS. Specifically, we aim to quantify the expression of three key glycolytic genes within bone-marrow derived mouse macrophages treated with PA, followed by LPS. Slc2a1 encodes for the transmembrane protein GLUT1 that allows glucose to enter the cell, and Hk2 and Pkfp encode for two rate-limiting enzymes in glycolysis. It is known that LPS upregulates glycolysis, and we hypothesize that PA induces trained immunity in macrophages by increasing expression of Slc2a1, Hk2, and Pkfp, and enhancing the inflammatory response to LPS. The capacity for PA to directly impact innate immune metabolism associated with inflammatory pathways may inform dietary interventions and treatments for sepsis patients, and our findings will be important to consider in a high SFA-fed population.

Biographies

Khaleda Aqaei, Biology; Minor: Community Health

KHALEDA AQAEI IS A SCHOLAR in the Ronald E. McNair Scholars Program and S-Stem at Portland State University, where she is pursuing a Bachelor of Science in Biology, and a minor in Community Health. She was born in Kabul, Afghanistan, a war-torn country where women are not allowed to pursue higher education, and grew up as a refugee in Iran for 15 years, where her education was also forbidden. Through these difficult times, she homeschooled herself independently up to 8th grade, and developed a passion for education that has inspired her to make a difference for women in her community. In 2011, she was accepted as a refugee to the U.S., and obtaining her GED at a Portland community college was the catalyst for great change in her life. Khaleda’s interest in biology and medicine was inspired by her father, who encouraged her to follow her dreams despite hardship. She aspires to become a physician and create change in underdeveloped countries like Afghanistan by addressing healthcare disparities, supporting minorities, and breaking down systemic barriers in education as an advocate for women’s rights. She speaks Farsi, Dari and is interested in learning Turkish. Currently, she works as a medical assistant at the Kartini Clinic to help children with autism and eating disorders, and is an undergraduate researcher in Dr. Brooke Napier’s lab. The goal of her research project is to determine the impact of palmitic acid, a dietary saturated fat, on glycolysis within mouse macrophages, and how this alters the cellular response to microbial products. She is interested in understanding how diets high in saturated fats modulate the host response to infections that lead to sepsis.

Dr. Brooke Napier, Faculty Mentor, Department of Biology

B. A. Napier, Ph.D. is an Assistant Professor within the Biology Department at Portland State University. She teaches Cell Biology and Immunology courses at PSU and serves as Editor at the FEMS journal Pathogens and Disease. Her laboratory is using a multifaceted approach to uncover the role of diet in reprogramming the immune response to infection and is necessary to develop efficacious dietary strategies to reduce metabolic inflammation and dietary interventions that improve outcomes of infection, acute inflammatory shock, and sepsis. Currently, Dr. Napier serves as the Graduate Student Mentorship Facilitator in Equity and Inclusion (CIMER Program) at PSU and active mentor for NIH EXITO and McNair Scholars.

Disciplines

Biology

Persistent Identifier

https://archives.pdx.edu/ds/psu/36201

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Aug 11th, 1:20 PM

Understanding the Metabolic Regulation of Trained Immunity by Palmitic Acid

Sepsis is an inflammatory disease that occurs when the body’s response to an infection becomes dysregulated, and infection-fighting processes of the body damage tissues via inflammation, resulting in organ failure and death. Currently, the role for diet in regulating sepsis susceptibility and severity is not fully understood. The Western Diet (WD), the most prevalent diet worldwide, is high in saturated fatty acids (SFAs) and sucrose, and low in fiber. Previously, we have used a lipopolysaccharide (LPS)-induced sepsis mouse model to show that mice fed a Western Diet (WD) or a diet enriched only in SFAs (Ketogenic Diet; KD), experience increased systemic inflammatory disease severity and mortality, compared to mice fed a low-SFA diet. It is unclear how dietary SFAs regulate inflammation during sepsis, however many SFAs have been shown to induce inflammation in monocytes and macrophages, key cell types that regulate inflammation during sepsis. Our preliminary data show that a pre-treatment with a specific dietary SFA, palmitic acid (PA), plays a role in amplifying the inflammatory response of monocytes and macrophages to a secondary challenge with numerous microbial ligands. This PA-induced hyper-inflammation resembles a well-known phenomenon called trained immunity. Trained immunity is a long-term immunological memory induced by a primary stimulus, which leads to hyper-inflammation upon secondary stimulation with a homologous or heterologous ligand. It is mediated by epigenetic and metabolic reprogramming that allows for modification of gene expression and cellular function. It is unknown if PA induces similar metabolic changes required for the induction of trained immunity. The goal of this study is to determine the metabolic pathways within macrophages that are perturbed by PA, and lead to enhanced inflammation upon secondary stimulation with LPS. Specifically, we aim to quantify the expression of three key glycolytic genes within bone-marrow derived mouse macrophages treated with PA, followed by LPS. Slc2a1 encodes for the transmembrane protein GLUT1 that allows glucose to enter the cell, and Hk2 and Pkfp encode for two rate-limiting enzymes in glycolysis. It is known that LPS upregulates glycolysis, and we hypothesize that PA induces trained immunity in macrophages by increasing expression of Slc2a1, Hk2, and Pkfp, and enhancing the inflammatory response to LPS. The capacity for PA to directly impact innate immune metabolism associated with inflammatory pathways may inform dietary interventions and treatments for sepsis patients, and our findings will be important to consider in a high SFA-fed population.