TLR3 promotes hepatocyte proliferation after partial hepatectomy by stimulating uPA expression and the release of tissue‐bound HGF

• Published in: The FASEB journal 2020-08, Vol.34 (8), p.10387-10397
• Main Authors: Stöß, Christian, Laschinger, Melanie, Wang, Baocai, Lu, Miao, Altmayr, Felicitas, Hartmann, Daniel, Hüser, Norbert, Holzmann, Bernhard
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - physiology; Extracellular Matrix - metabolism; Extracellular Matrix - physiology; Hepatectomy - methods; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - physiology; Hepatocyte Growth Factor - metabolism; Hepatocytes - metabolism; HGF; Liver - metabolism; liver regeneration; Liver Regeneration - physiology; Male; Mice; Mice, Inbred C57BL; Organogenesis - physiology; stellate cells; TLR3; Toll-Like Receptor 3 - metabolism; Urokinase-Type Plasminogen Activator - metabolism; urokinase‐type plasminogen activator
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202000904R

TLR3 is implicated in anti‐viral immune responses, but may also act as a sensor of tissue damage in the absence of infection. Here, we provide evidence for an essential role of TLR3 in liver regeneration after an acute loss of tissue due to partial hepatectomy. Mice lacking TLR3 had a severe and sustained defect in the restoration of liver tissue with reduced liver‐to‐body weight ratios even after an extended recovery period of 2 weeks. Hepatocyte cell cycle progression into S phase was impaired in TLR3‐deficient mice. Mechanistic analyses revealed that TLR3‐deficient mice had markedly reduced systemic levels of active HGF, but had increased amounts of inactive tissue‐bound HGF. Importantly, expression of uPA, which orchestrates the processing and release of HGF from the hepatic extracellular matrix, was reduced in regenerating livers of TLR3‐deficient mice. In addition, expression of the HGF maturation factor HGFAC was transiently diminished in TLR3‐deficient mice. In vitro, engagement of TLR3 directly stimulated expression of uPA by hepatic stellate cells. Thus, TLR3 supports liver regeneration through upregulation of uPA, which promotes the release of preformed HGF from extracellular matrix stores.