First Advisor

Brooke Anne Napier

Term of Graduation

Summer 2024

Date of Publication

6-27-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Biology

Department

Biology

Language

English

Physical Description

1 online resource (x, 135 pages)

Abstract

Nutrition, cellular metabolism, and inflammatory regulation of the immune system are interconnected, and advancing our understanding of this will greatly improve treatment of metabolic and inflammatory disease. Specifically, dietary saturated fats are becoming increasingly appreciated for their ability to modify innate immune cell function in mammals following absorption into the blood and lymphatic circulation systems. The work herein focuses on the capacity for lipids in the diet to modulate innate immune memory. My thesis first broadly outlines fundamental background, including: the evolution of human nutrition, the discovery of innate immune memory, and key topics that reoccur throughout the text surrounding dietary modulation of innate immunity, and the implications this has for treating disease. Next, I review the trek of dietary fat from digestion to blood and lymph, to the inside of a white blood cell and the inner workings of mitochondrial metabolism—where breakdown occurs, and byproducts travel to the nucleus to unwind or tighten chromatin. The overarching impact of this is an alteration in the way genes that encode inflammatory proteins are made more or less available for transcription. The cellular mechanisms underlying these processes are currently burgeoning in the field of immunometabolism, and the research is important for identifying biomarkers and novel therapeutic targets for treating diseases characterized by systemic inflammation, including obesity, insulin resistance, atherosclerosis, autoimmunity, and sepsis.

A large portion of the experimental work that went into this shows how diet-induced innate immune memory subsequently changes the severity and outcome of disease using mouse models of acute, systemic inflammation. These experiments reveal how chronic exposure to dietary saturated fats alters inflammation in the blood and worsens systemic inflammation induced by a microbial ligand. The cell culture models used were designed to mimic primary and secondary stimulation of innate immune cells as would occur with diet exposure followed by microbial ligand stimulation. An infection model using a fungal pathogen is utilized to bolster these findings.

Chronic exposure to a diet enriched in saturated fatty acids derived from milkfat is shown here to significantly alter the bone marrow compartment in mice. Specifically, palmitic acid, which is common in many human diets across the globe and consequently found also in the blood, shows a unique capacity for modulating memory responses in macrophages derived from the bone marrow, indicative of the phenomenon known as trained immunity. Exposing mice to palmitic acid alone is enough to alter the outcome of systemic inflammatory disease, and infection with a fungal pathogen. Interestingly, this impact is reversible in vitro and in vivo using another fatty acid simultaneously that is also common in our diets and blood, the unsaturated oleic acid. This remarkable quality of lipids that regulate inflammation and subsequent disease outcome has great potential to contribute to better treatments for metabolic and inflammatory diseases.

Rights

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

Persistent Identifier

https://archives.pdx.edu/ds/psu/42531

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