Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors (PRR) that play a key role in innate and adaptive immunity by recognizing structural components unique to bacteria, fungi and viruses. TLR4 is the most studied of the TLRs, and its primary exogenous ligand is lipopolysaccharide, a component of Gram-negative bacterial walls. In the absence of exogenous microbes, endogenous ligands including damage-associated molecular pattern molecules from damaged matrix and injured cells can also activate TLR4 signaling. In humans, single nucleotide polymorphisms of the TLR4 gene have an effect on its signal transduction and on associated risks of specific diseases, including cirrhosis. In liver, TLR4 is expressed by all parenchymal and non-parenchymal cell types, and contributes to tissue damage caused by a variety of etiologies. Intact TLR4 signaling was identified in hepatic stellate cells (HSCs), the major fibrogenic cell type in injured liver, and mediates key responses including an inflammatory phenotype, fibrogenesis and anti-apoptotic properties. Further clarification of the function and endogenous ligands of TLR4 signaling in HSCs and other liver cells could uncover novel mechanisms of fibrogenesis and facilitate the development of therapeutic strategies.

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Objective-We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells, and assessed the prognostic capability of their expression in cirrhosis.Design-We defined a hepatic stellate cell gene signature by comparing stellate, immune, and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables, using overall survival as the primary clinical outcome. This signature was derived in a retrospective-prospective cohort of hepatitis Crelated early-stage cirrhosis (prognostic index derivation set), and validated in an independent retrospective cohort of post-resection HCC patients (n=82, prognostic index validation set). We then examined association between hepatic stellate cell signature expression and decompensation, hepatocellular carcinoma (HCC) incidence, and progression of Child-Pugh class as additional outcomes in the prognostic index derivation set, and HCC recurrence as an additional outcome in the validation set. We tested whether hepatic stellate cell signature expression is predictive of Results-The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors, and correlates with the extent of fibrosis in human, mouse, and rat datasets. The hepatic stellate cell signature contains several cell surface genes previously established as stellate cell-specific, as well as PCDH7, a novel protocadherin stellate cell surface marker. Importantly, association of clinical prognostic variables with overall survival (c-index: 0.66, 95% CI: 0.59-0.74) was improved by adding the hepatic stellate cell signature (cindex: 0.70, 95%CI: 0.62-0.78); we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival Conclusion-This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting, and isolation. Hepatic stellate cell signature expression may identify HCV cirrhosis or post resection HCC patients with poor prognosis.