Macrophage Activation Profile and Phenotype Are Regulated by Metabolic Pathways and Are Altered by Diabetic Conditions
Guest, Christopher B.
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Permalink
https://hdl.handle.net/2142/87900
Description
Title
Macrophage Activation Profile and Phenotype Are Regulated by Metabolic Pathways and Are Altered by Diabetic Conditions
Author(s)
Guest, Christopher B.
Issue Date
2008
Doctoral Committee Chair(s)
Keith Kelley
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Immunology
Language
eng
Abstract
The incidence of type 2 diabetes is rapidly expanding. Some of the more obvious pathologies associated with it include: defective glucose metabolism, obesity, cardiovascular disease and an inability to mount an effective immune response to infection by certain pathogenic organisms, leading to sepsis and death. A common tie linking these seemingly disparate complications is chronic inflammation. Today we know that inflammation is regulated locally and systemically by numerous mechanisms. One of the most important of these regulators is the macrophage. Macrophages are the bridge between the adaptive and innate immune system and are capable of assuming numerous phenotypes depending on the microenvironment, some proinflammatory and others anti-inflammatory. These relationships are detailed in the review of literature. Our group has previously shown that PKCdelta is a critical regulator of macrophage differentiation; however, many of the factors that determine macrophage phenotype are unknown at this time. Chapter two illustrates the novel finding that one of the master metabolic pathways (CaMKK/AMPK) acts as a key regulator of macrophage activation by controlling the expression of CD86, CD11b, TNF-alpha and IL-10. Given the apparent importance of metabolic pathways in determining the macrophage activation profile, we attempted to identify important phenotypic variations caused by diabetes. Cardiovascular disease is the leading cause of death in those with diabetes. Macrophages play an essential role in the development of atherosclerosis by accumulating lipids and becoming proinflammatory foam cells. In chapter three we demonstrate that diabetes enhanced the expression of CD36 and SR-A and the accumulation of cholesteryl ester and acetylated-LDL in primary mouse macrophages to form foam cells similar to those found in atherosclerotic plaques. Finally, macrophages must be capable of integrating numerous metabolic and immune signals. One way they do this is by sampling large amounts of bulk fluid in the local environment by an energy dependent process called macropinocytosis. Chapter four provides evidence that macropinocytosis is decreased in peritoneal macrophages from diabetic mice. Since diabetes is characterized by metabolic abnormalities and altered immune function we tested the effect of hyperglycemia and hyperinsulinemia on macropinocytosis. Importantly, macrophages cultured in diabetic conditions also had decreased macropinocytosis and evidence supports that it is controlled by AMPK. Taken together these findings indicate that metabolic pathways regulate macrophage function and show the important balance and interdependence of immunity and metabolism in the pathology of diseases like obesity and diabetes.
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