Abstract
BackgroundIntact Toll-like receptor 4 (TLR4) has been identified in hepatic stellate cells (HSCs), the primary fibrogenic cell type in liver. Here, we investigated the impact of TLR4 signaling on the gene expression network of HSCs by comparing the transcriptomic changes between wild-type (JS1) and TLR4 knockout (JS2) murine HSCs in response to two TLR4 ligands, lipopolysacchride (LPS), or high-mobility group box 1 (HMGB1).ResultsWhole mouse genome microarray was performed for gene expression analysis. Gene interaction and co-expression networks were built on the basis of ontology and pathway analysis by Kyoto Encyclopedia of Genes and Genomes (KEGG). Gene expression profiles are markedly different between Wild type (JS1) and TLR4 knockout (JS2) HSCs under basal conditions or following stimulation with LPS or HMGB1. The differentially expressed genes between TLR4 intact and null HSCs were enriched in signaling pathways including p53, mTOR, NOD-like receptor, Jak-STAT, chemokine, focal adhesion with some shared downstream kinases, and transcriptional factors. Venn analysis revealed that TLR4-dependent, LPS-responsive genes were clustered into pathways including Toll-like receptor and PI3K-Akt, whereas TLR4-dependent, HMGB1-responsive genes were clustered into pathways including metabolism and phagosome signaling. Genes differentially expressed that were categorized to be TLR4-dependent and both LPS- and HMGB1-responsive were enriched in cell cycle, ubiquitin mediated proteolysis, and mitogen-activated protein kinase (MAPK) signaling pathways.ConclusionsTLR4 mediates complex gene expression alterations in HSCs. The affected pathways regulate a wide spectrum of HSC functions, including inflammation, fibrogenesis, and chemotaxis, as well as cell growth and metabolism. There are common and divergent regulatory signaling downstream of LPS and HMGB1 stimulation via TLR4 on HSCs. These findings emphasize the complex cascades downstream of TLR4 in HSCs that could influence their cellular biology and function.Electronic supplementary materialThe online version of this article (doi:10.1186/s13069-016-0039-z) contains supplementary material, which is available to authorized users.
Highlights
Intact Toll-like receptor 4 (TLR4) has been identified in hepatic stellate cells (HSCs), the primary fibrogenic cell type in liver
We have explored the broad impact of TLR4 signaling on HSC gene expression and signaling pathways and the common and differential effects of the TLR4 activation by LPS or high-mobility group box 1 (HMGB1), which represent the exogenous and endogenous ligands of TLR4, respectively
Comparison of the transcriptome of JS1 and JS2 cells The transcriptomic changes within wild-type (JS1) and TLR4 knockout (JS2) mouse stellate cell lines were investigated
Summary
Intact Toll-like receptor 4 (TLR4) has been identified in hepatic stellate cells (HSCs), the primary fibrogenic cell type in liver. Hepatic stellate cells (HSCs) are the predominant extracellular matrix-producing cell type in the liver [1,2,3,4,5]. The activation of HSCs is the central event in fibrogenesis that drives fibrosis, cirrhosis, and hepatic decompensation. The activated HSC adopts a myofibroblast-like phenotype to produce collagen and other extracellular matrix (ECM) components. Activated HSCs are resistant to apoptotic stimuli and express pattern recognition receptors, Toll-like receptors 4 (TLR4) and 9 (TLR9), and respond to their ligands to activate downstream signalling pathways and transcriptional factors (TFs)
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