TLR3 promotes hepatocyte proliferation after partial hepatectomy by stimulating uPA expression and the release of tissue-bound HGF.
Animals
Cell Proliferation
/ physiology
Extracellular Matrix
/ metabolism
Hepatectomy
/ methods
Hepatic Stellate Cells
/ metabolism
Hepatocyte Growth Factor
/ metabolism
Hepatocytes
/ metabolism
Liver
/ metabolism
Liver Regeneration
/ physiology
Male
Mice
Mice, Inbred C57BL
Organogenesis
/ physiology
Toll-Like Receptor 3
/ metabolism
Urokinase-Type Plasminogen Activator
/ metabolism
HGF
TLR3
liver regeneration
stellate cells
urokinase-type plasminogen activator
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
15
04
2020
revised:
15
05
2020
accepted:
21
05
2020
pubmed:
17
6
2020
medline:
2
3
2021
entrez:
16
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32539223
doi: 10.1096/fj.202000904R
doi:
Substances chimiques
HGF protein, mouse
0
TLR3 protein, mouse
0
Toll-Like Receptor 3
0
Hepatocyte Growth Factor
67256-21-7
Urokinase-Type Plasminogen Activator
EC 3.4.21.73
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
10387-10397Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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