Regulation of Macrophage Function through Control of Lipid and Glucose Metabolism: Roles in Inflammation and Redox Homeostasis.

Macrophages are innate immune cells which have an unparalleled diversity of functions in health and disease, fueled by their remarkable ability to change their phenotype in response to diverse environmental stimuli. Critical to macrophage function is their ability to control their cellular metabolism, which not only provides energy for the cell but also unique fuels required for specific macrophage functions.
Here we examine the roles of lipid and glucose metabolism in the control of macrophage function, particularly as it pertains to their response to inflammation and oxidative stress. In the first part of this dissertation, we interrogate the role of acetyl-CoA carboxylase (ACC), the committed step of fatty acid biosynthesis, in macrophage acute and chronic inflammation. We find that loss of ACC impairs the acute inflammatory response but is dispensable for the chronic inflammation observed in metabolic syndrome. In the second part of this dissertation, we attempt to understand how macrophages regulate their metabolism in order to limit the oxidative stress of heme degradation and uncover a necessity of glucose shuttling through the pentose phosphate pathway for macrophage heme clearance. We then examine how macrophage metabolism regulates heme-induced inflammation and oxidative stress in the context of Sickle Cell Disease.
In summary, this work uncovers as-yet unappreciated roles for control of glucose and lipid metabolism in control of macrophage inflammatory and antioxidant function, reinforcing the importance of macrophage metabolism in the pathophysiology of diverse diseases and identifying novel targets for therapeutic treatment of pathological inflammation.