Regulation of innate liver injury by TLR9

Abstract

The inflammatory response to hepatocyte death is mediated by TIR-domain containing adapters, which are involved in pattern recognition receptor (PRR) signaling. We study this mechanism during acute liver injury in mice, induced by Diphtheria Toxin (DT) in cells that have been transduced with the human DT receptor. Dying cells promote a local innate immune response in several different ways, including chemokine production, inflammasome activation, and PRR stimulation. Toll-like receptor 9 (TLR9), a PRR that interacts with the TIR-domain containing adapter MyD88, has been implicated in models of both acute liver failure and chronic liver disease. However, the role of TLR9 in DT-induced acute liver injury has not yet been determined. TLR9 deletion exacerbated liver injury compared to WT mice by 48 hours post-DT treatment. TLR9 deletion also had cell type specific effects in steady state liver, most notably in hepatocyte programmed cell death gene expression. Fas gene expression was increased in TLR9-deficient mice, while inhibition of TLR9 in vitro caused elevated Fas and FasL expression in a hepatocyte-derived cell line. In this thesis, we argue that TLR9 is hepatoprotective during acute liver inflammation by controlling Fas hepatotoxicity. In addition, we briefly discuss the impact of TLR9 deletion on chemokine gene expression in purified hepatocytes and Kupffer cells, and the impact of Silymarin treatment on the inflammatory response to DT-induced hepatocyte death.