Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer.
Animals
Apoptosis
/ genetics
Endothelial Cells
/ metabolism
Female
Genome-Wide Association Study
Liver
/ injuries
Male
Mice
Mice, Inbred C57BL
Phagocytosis
/ genetics
Proto-Oncogene Proteins
/ genetics
Receptor Protein-Tyrosine Kinases
/ antagonists & inhibitors
Signal Transduction
/ genetics
c-Mer Tyrosine Kinase
/ genetics
Axl Receptor Tyrosine Kinase
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
11
03
2020
revised:
28
05
2020
accepted:
29
05
2020
entrez:
24
6
2020
pubmed:
24
6
2020
medline:
15
7
2021
Statut:
epublish
Résumé
Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.
Identifiants
pubmed: 32571802
pii: 3/8/e202000694
doi: 10.26508/lsa.202000694
pmc: PMC7335405
pii:
doi:
Substances chimiques
Proto-Oncogene Proteins
0
Mertk protein, mouse
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
c-Mer Tyrosine Kinase
EC 2.7.10.1
Axl Receptor Tyrosine Kinase
0
AXL receptor tyrosine kinase, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI101400
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS085296
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG060748
Pays : United States
Informations de copyright
© 2020 Zagórska et al.
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