Macrophage Regulation in the Murine Inflammatory Response

Abstract

The development of acute and chronic liver disease is a complex condition involving the dysregulation of hepatic metabolism and the accumulation of critical immune cells; specifically, the recruitment and activation of macrophages. The relationship between lipid accumulation, cytokine expression, and hepatic macrophages remains an area of further study. The purpose of these studies was to assess the role of the macrophage in the context of liver disease. Various mechanistic studies involving genetic mouse models of liver disease including alcoholic (ALD), nonalcoholic (NAFLD) and toxin-induced hepatitis were used to replicate the multiple variables associated with a hepatic immune response. Further, cellular based studies using bone marrow derived macrophages (BMDMs) and isolated Kupffer cells (KCs) were used to verify whole animal data in areas of immune cell regulation. Fatty acid binding proteins (FABPs) are becoming recognized as key regulators of both the inflammatory response and lipid metabolism. Therefore, the effect FABP1 and FABP5 deletion on the early signs of liver injury associated with ethanol exposure in mice were first investigated. These studies demonstrated that FABP1, but not FABP5, regulates hepatic lipid accumulation and inflammation in the context on ALD. On the other hand, FABP5 is highly expressed in macrophages and may play an important role in the hepatic inflammatory response after endotoxin (LPS) exposure in mice. Specifically, these findings demonstrate that loss of FABP5 promotes a more anti-inflammatory response in the macrophage. Lastly, we focused on the hypothesis that Dicer regulates the development of a unique macrophage population that facilitates the resolution of hepatic fibrosis. We found that loss of Dicer in the macrophage delays hepatic fibrosis repair. In summary, this dissertation discusses the mechanisms of innate immune cell activation and the regulation of macrophage function in relation to acute and chronic liver injury. Further, these studies demonstrate that macrophages are an integral component of the immune system which delicately regulate hepatic metabolism and inflammatory and anti-inflammatory processes in the context of liver disease.