Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

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 prominen...

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Bibliographic Details
Published in:Life science alliance 2020-08, Vol.3 (8), p.e202000694
Main Authors: Zagórska, Anna, Través, Paqui G, Jiménez-García, Lidia, Strickland, Jenna D, Oh, Joanne, Tapia, Francisco J, Mayoral, Rafael, Burrola, Patrick, Copple, Bryan L, Lemke, Greg
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Axl Receptor Tyrosine Kinase
c-Mer Tyrosine Kinase - genetics
c-Mer Tyrosine Kinase - metabolism
Endothelial Cells - metabolism
Female
Genome-Wide Association Study
Liver - injuries
Liver - metabolism
Liver - pathology
Male
Mice
Mice, Inbred C57BL
Phagocytosis - genetics
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Signal Transduction - genetics
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Summary: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.
ISSN:2575-1077
2575-1077
DOI:10.26508/LSA.202000694