Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators.
CM, conditioned medium
ECM, extracellular matrix
Gas-6
Gas-6, growth arrest-specific gene 6
HSC(s), hepatic stellate cells
KC(s), Kupffer cell(s)
M-CSF, macrophage colony-stimulating factor
M2c-like macrophages
MerTK, Myeloid-epithelial-reproductive tyrosine kinase
NAFLD, non-alcoholic fatty liver disease
NASH
NASH, non-alcoholic steatohepatitis
PMA, phorbol 12-myristate 13-acetate
TGFβ1, transforming growth factor-β1
THP-1
TIMP1, tissue inhibitor of metalloproteinase 1
VEGF-A, vascular endothelial growth factor-A
liver fibrosis
siRNA, small-interfering RNA
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
01
02
2021
revised:
29
12
2021
accepted:
04
01
2022
entrez:
7
3
2022
pubmed:
8
3
2022
medline:
8
3
2022
Statut:
epublish
Résumé
Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs.
METHODS
METHODS
Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK
RESULTS
RESULTS
Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK
CONCLUSIONS
CONCLUSIONS
MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis.
LAY SUMMARY
BACKGROUND
Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue.
Identifiants
pubmed: 35252828
doi: 10.1016/j.jhepr.2022.100444
pii: S2589-5559(22)00016-7
pmc: PMC8891698
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100444Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest to disclose related to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details.
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