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CHARACTERIZING CELL INTERACTIONS THROUGH CHEMOKINE RECEPTORS TO MEDIATE HEPATOCYTE RECOVERY AND RESOLUTION OF INFLAMMATION AFTER ACETAMINOPHEN INDUCED-LIVER INJURY
Nguyen, Nga Thi
Nguyen, Nga Thi
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Abstract
Acetaminophen (APAP) is a common analgesic, but overdose of the drug is the main cause of acute liver failure in the United States and other Western countries. The mechanism of APAP-induced liver injury has been well characterized and involves the formation of reactive oxygen species and mitochondrial dysfunction leading to necrotic cell death and initiates sterile inflammation. Infiltration of neutrophils and monocytes into the hepatic parenchyma is the hallmark of the innate immune responses after an APAP overdose. While the dynamic of local tissue environment, represented by orchestration of immune cells and hepatocytes are critical for liver recovery and resolution, the direct interactions between these cells to facilitate tissue repair remain unclear. The aim of this dissertation is to investigate the molecular interactions between macrophages and hepatocytes mediated through chemokine receptors, CXCR2 and CXCR4, in liver recovery and inflammation resolution after APAP-induced liver injury. We first describe a comparison of the innate immune response after the moderate and severe APAP overdose. Our data indicate a delay in monocyte recruitment and a complete disappearance of Kupffer cells after severe overdose. In contrast, neutrophils were dominant throughout the course of injury, and preventing neutrophil infiltration protected against liver injury in the severe APAP overdose but not moderate overdose. This study suggests the lack of cell interactions and the magnitude of hepatocyte injury change neutrophil behaviors. Given the importance of having this orchestration of immune cells to liver recovery, the rest of this dissertation research used the moderate APAP overdose (300mg/kg APAP) where Kupffer cells, monocyte-derived macrophages and neutrophils are present within the liver before the initiation of liver repair. After moderate APAP overdose in mice, we demonstrate that CXCR2 is selectively induced on proliferating hepatocytes surrounding the necrotic area which enhances hepatocyte recovery through upregulation of chemotaxis genes such as CXCL14. In addition, the interaction between hepatocytes and Kupffer cells is described, whereby production of IL-10 by Kupffer cells induces CXCR2 on hepatocytes. This study demonstrated a critical interaction that Kupffer cell exerts on hepatocytes to promote liver repair. We also identified CXCL14, a newly recognized chemokine, with unknown receptors, in the pathophysiology. Our data indicate CXCL14 levels are strongly elevated in plasma of non-surviving APAP overdose patients, and thus can be used as a predictive biomarker for negative outcome in acute liver failure patients. In parallel, animal studies show CXCL14 is upregulated after administration of a severe overdose of APAP and produced mainly by hepatocytes. Finally, as the hepatocytes recovered, inflammation resolution is initiated to limit overactivation of immune cells. The last part of this dissertation demonstrates the clearance process of Kupffer cells which normally are present in the portal vein area. We showed that centrilobular Kupffer cells undergo apoptosis starting at 72 hours after APAP treatment. In addition, we investigated the role of chemokine receptor CXCR4 in mediating macrophage apoptosis. The interaction between hepatocytes and macrophages were illustrated in this study through secretion of TGF-β1 which induced CXCR4 expression on macrophages. Collectively, this dissertation demonstrates critical interactions between hepatocytes and macrophages to promote hepatocyte recovery and inflammation resolution after APAP overdose. During the recovery phase, proliferating hepatocytes regulate immune cell activities through production of chemokines and cytokines. In the resolution phase, recovered hepatocytes promote immune cell clearance to restore homeostasis.
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2022-08-31
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University of Kansas
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Toxicology,