Special report and reviewToll-Like Receptor Signaling in the Liver
Section snippets
TLRs and Coreceptors
The human TLR family consists of currently 10 members, which are structurally characterized by the presence of a leucine-rich repeat (LRR) domain in their extracellular domain and a Toll/interleukin (IL)-1 receptor (TIR) domain in their intracellular domain. The existence of a large number of TLRs enables the innate immune system to discriminate between PAMPs that are characteristic of different microbial classes and launch specific defense mechanisms. A comparison of the amino acid sequences
Intracellular Adapter Molecules and Downstream Pathways
Four adapter molecules interact with the TIR domains of TLRs to transduce proinflammatory and antiviral signals (Figure 1). Among these, MyD88 is the adapter molecule that is involved in the majority of pathways, which has led to classifying downstream signaling pathways as “MyD88-dependent” and “MyD88-independent.”
MyD88 interacts with TLR1, TLR2, TLR4, TLR5, TLR6, TLR7, and TLR9 as well as the IL-1 and IL-18 receptors. MyD88 has an N-terminal death domain and a C-terminal TIR domain through
Kupffer Cells
Kupffer cells are resident macrophages of the liver and perform multiple functions, including phagocytosis and antigen processing and presentation, and secrete proinflammatory mediators, including cytokines, prostanoids, nitric oxide, and reactive oxygen intermediates. Because of their anatomical localization, Kupffer cells are among the first cells in the liver to be hit by gut-derived toxins and orchestrate the inflammatory response within the liver. Kupffer cells express TLR4 and are
Alcohol-Induced Liver Injury
Orally ingested alcohol disrupts the intestinal epithelial barrier causing enhanced permeability87 and subsequent elevations of endotoxin levels in the portal vein.88, 89 LPS-mediated activation of Kupffer cells plays a crucial role in ethanol-induced liver injury (Figure 3). Liver injury is strongly reduced when gram-negative microflora is eliminated from the gut by lactobacillus or antibiotics or when Kupffer cells are depleted with gadolinium chloride.90, 91, 92 Conversely, long-term ethanol
Conclusion and Future Directions
TLR-mediated signals play an important role in the pathophysiology of a number of hepatic diseases. TLR4 and its ligand LPS are involved in alcoholic liver disease and hepatic fibrogenesis. TLR4 and its downstream mediator IRF3 are crucial mediators of injury after hepatic ischemia-reperfusion. The TRIF-TBK1-IRF3 pathway is targeted by HCV to down-regulate immune responses and establish persistent infection. However, there is still a big gap in our knowledge about the role of TLRs in many
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Supported by a Research Scholar Award from the American Gastroenterological Association and Procter & Gamble (to R.F.S.).