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Toll-like receptor signaling and liver fibrosis.

Aoyama T, Paik YH, Seki E - Gastroenterol Res Pract (2010)

Bottom Line: Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host.The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine.Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive MC# 0702, Leichtag Biomedical Research Building Rm# 332 MM, La Jolla, CA 92093-0702, USA.

ABSTRACT
Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

No MeSH data available.


Related in: MedlinePlus

TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.
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fig1: TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.

Mentions: TLR4 signaling activates NF-κB and JNK/AP-1 pathways through MyD88 and TRIF [15]. TLR4-mediated downregulation of Bambi expression requires the activation of NF-κB and partially JNK through MyD88, but not TRIF, in HSCs. Indeed, Bambi expression was downregulated in WT and TRIF−/− HSCs, but not in MyD88−/−, NF-κB, or JNK inactivated HSCs after LPS stimulation (E.S. unpublished observation) [10]. Similarly, MyD88−/−, but not TRIF−/−, mice demonstrated reduced fibrogenic gene expression at the early phase after BDL, whereas both MyD88−/− and TRIF−/− mice had reduced liver fibrosis at the late phase of liver fibrosis [10]. These findings suggest that MyD88 is crucial for the Bambi-regulated liver fibrosis, whereas TRIF regulates fibrogenic responses independently of Bambi, at least at the chronic stage. Taken together, TLR4 signaling is crucial in the activation of HSCs during liver fibrosis. Intestinal microflora is a major source of LPS as a ligand for TLR4 in liver fibrosis. TLR4 signaling in HSCs enhances the recruitment of inflammatory cells and downregulates Bambi for fibrogenic response Figure 1.


Toll-like receptor signaling and liver fibrosis.

Aoyama T, Paik YH, Seki E - Gastroenterol Res Pract (2010)

TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913673&req=5

fig1: TLR4 signaling enhances TGF-β signaling in hepatic stellate cells. Upon liver injury, intestinal permeability is increased due to the intestinal dysbiosis and tight junction disintegrity, which allows microflora-derived LPS into the portal vein. This LPS stimulates TLR4 on hepatic stellate cells (HSCs). Quiescent HSCs express high levels of Bambi which restricts TGF-β signaling. TLR4 stimulation leads to the production of various chemokines (MCP-1, MIP-1β, and RANTES) in HSCs, recruiting Kupffer cells through their CCR1 and CCR2. Recruited Kupffer cells produce TGF-β which binds to TGF-β receptor type I in HSCs. Simultaneously, TLR4 signaling downregulates Bambi expression through MyD88 and NF-κB in HSCs. HSCs become free from restricted TGF-β signaling by the downregulation of Bambi, which eventually induces HSC activation.
Mentions: TLR4 signaling activates NF-κB and JNK/AP-1 pathways through MyD88 and TRIF [15]. TLR4-mediated downregulation of Bambi expression requires the activation of NF-κB and partially JNK through MyD88, but not TRIF, in HSCs. Indeed, Bambi expression was downregulated in WT and TRIF−/− HSCs, but not in MyD88−/−, NF-κB, or JNK inactivated HSCs after LPS stimulation (E.S. unpublished observation) [10]. Similarly, MyD88−/−, but not TRIF−/−, mice demonstrated reduced fibrogenic gene expression at the early phase after BDL, whereas both MyD88−/− and TRIF−/− mice had reduced liver fibrosis at the late phase of liver fibrosis [10]. These findings suggest that MyD88 is crucial for the Bambi-regulated liver fibrosis, whereas TRIF regulates fibrogenic responses independently of Bambi, at least at the chronic stage. Taken together, TLR4 signaling is crucial in the activation of HSCs during liver fibrosis. Intestinal microflora is a major source of LPS as a ligand for TLR4 in liver fibrosis. TLR4 signaling in HSCs enhances the recruitment of inflammatory cells and downregulates Bambi for fibrogenic response Figure 1.

Bottom Line: Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host.The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine.Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, 9500 Gilman Drive MC# 0702, Leichtag Biomedical Research Building Rm# 332 MM, La Jolla, CA 92093-0702, USA.

ABSTRACT
Liver fibrosis occurs as a wound-healing scar response following acute and chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, hepatitis B and C, and autoimmune hepatitis. Myofibroblasts, mainly transdifferentiated from hepatic stellate cells, are pivotal cell types that produce fibrillar collagen. The activation of inflammatory cells, including Kupffer cells, is a crucial step for activating hepatic stellate cells. Toll-like receptors (TLRs) are pattern recognition receptors that sense pathogen-associated molecular patterns (PAMPs), which discriminate the products of microorganisms from the host. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes in the liver. TLR signaling induces potent innate immune responses in these cell types. The liver is constantly exposed to PAMPs, such as LPS and bacterial DNA through bacterial translocation because there is a unique anatomical link, the portal vein system between liver and intestine. Recent evidence demonstrates the role of TLRs in the activation of hepatic immune cells and stellate cells during liver fibrosis. Moreover, crosstalk between TLR4 signaling and TGF-beta signaling in hepatic stellate cells has been reported. This paper highlights the role of TLR signaling in stellate cell activation and the progression of liver fibrosis.

No MeSH data available.


Related in: MedlinePlus