Crispe, Ian NBrempelis, Katherine2016-04-062016-04-062016-03Brempelis_washington_0250E_15601.pdfhttp://hdl.handle.net/1773/35509Thesis (Ph.D.)--University of Washington, 2016-03Acute and chronic liver disease are estimated to have caused more than two million deaths in 2013, accounting for 4% of total worldwide deaths. The etiologies of acute and chronic liver injury are varied and include insult from pathogens, toxins, diet, and mechanical stresses. A common feature of both infectious and non-infectious liver injury is the death of hepatocytes, the dominant cell population in the liver. The innate inflammatory response to hepatocyte death plays an important role in the outcome of liver injury and can determine whether inflammation is resolved or progresses to chronic disease. This dissertation outlines research to identify innate immune signaling pathways involved in the response to hepatocyte death. To this end, we have developed a mouse model of hepatocyte-specific death to induce acute liver injury by expressing the human diphtheria toxin receptor specifically in hepatocytes. Upon administration of diphtheria toxin and induction of hepatocyte death, we found that the Toll/IL-1 receptor domain-containing adapter protein inducing IFN-β (TRIF) was a central mediator in the resulting inflammatory response and signaled by Toll-like receptor 4- and type I interferon-independent mechanisms. Hepatocytes were the main responders to cell death and up-regulated chemokine (Ccl2, Ccl5, Ccl7, Cxcl1, Cxcl2, Cxcl10), cell adhesion (Icam1, Vcam1), and inflammatory (Tnf, Ifnb1) genes more than either liver sinusoidal endothelial cells or Kupffer cells. We also employed a diet- and alcohol- induced model of liver injury to study the effects of hepatocyte death in a chronic setting. We found that increased liver steatosis, or fatty liver, correlated with increased amounts of dietary carbohydrates, and specifically glucose. Furthermore, similar to our model of acute liver injury, we found that hepatocytes were central responders to liver injury and up-regulated the expression of chemokine (Ccl2, Ccl5, Cxcl10), cell adhesion (Vcam1), inflammatory (Il1a, Il1b), and fibrosis (Mmp9, Mmp12, Pdgfra, Tgfb1) genes more than either liver sinusoidal endothelial cells or Kupffer cells. Finally, ethanol exposure increased the recruitment of neutrophils to the liver but down-regulated expression of Tgfb1 and reduced the overall pathology. The unifying theme we demonstrate in this thesis is the previously-underappreciated central role that hepatocytes play in the response to non-infectious liver injury. Hepatocytes are both the targets of insult and the primary mediators of the innate immune response in models of acute and chronic inflammation, suggesting a conserved mechanism in the response to liver injury.application/pdfen-UShepatocyte; liver injury; sterile inflammationImmunologyglobal healthThesis