All ETDs from UAB

Advisory Committee Chair

Timothy Garvey

Advisory Committee Members

Yuchang Fu

Joanne Murphy-Ullrich

Suzanne Michalek

Rakesh Patel

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Atherosclerosis is disease characterized by dysregulated lipid metabolism and chronic inflammation. Macrophages are critical to the progression of the disease and are involved in the pathophysiology at all stages of the disease. In the early stages, macrophages are responsible for fatty streak formation by becoming foam cells through lipid uptake. In the later stages, macrophages contribute to the degradation of the fibrous cap and are largely responsible for chronic inflammation in atherosclerotic plaques. Tribbles homolog 3 (TRB3) is a pseudokinase that inhibits Akt activation by blocking its phosphorylation site. TRB3 is expressed on numerous cell types in the body (pancreatic beta cells, hepatocytes, adipocytes and skeletal muscle) and it has been implicated in various processes including ER stress, insulin signaling, and cell differentiation. We were interested in the expression of and the function of TRB3 in macrophages, and establishing a novel role for TRB3 in the area of macrophage biology. We found that TRB3 is expressed by macrophages. Its expression can be induced by oxidized low-density lipoprotein (oxLDL), lipopolysaccharide (LPS), minimally-modified low-density lipoprotein (mmLDL) and even hypoglycemia. Upon determining a few of the factors that influence TRB3 expression in macrophages we wanted to investigate how changes in its expression would affect foam cell formation. TRB3 levels above and below basal expression increased the macrophage’s capacity to uptake modified lipoproteins. While these macrophages accumulated more cholesterol, they secreted less pro-inflammatory cytokines. By increasing the macrophage’s role in cholesterol accumulation, we have shown that there is a tradeoff in its inflammatory potential. We also tested this hypothesis in NLRP3-/- macrophages, which have been shown to have a decreased inflammatory response to exogenous stimuli, and determined that a similar reciprocal regulation occurs in these macrophages with impaired inflammasome activity. Taken together, these studies provide novel insight into a mechanism resulting in macrophage heterogeneity in atherosclerosis. We believe that TRB3 has the ability to influence the M1 versus M2 macrophage phenotype, which will be important in further identifying how macrophages influence the progression of atherosclerotic disease.

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