Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.
OBJECTIVE
Resident macrophages and myofibroblasts derived from hepatic stellate cells play a key role in liver wound healing. We previously reported that these sinusoidal cells secrete the growth arrest-specific protein 6 (Gas6) and express Axl, one of its receptors. Here we address the role of Gas6 in the healing process during acute liver injury.


METHODS
Toxic hepatitis was induced by a single carbon tetrachloride injection in Gas6 deficient (Gas6(-/-)) mice and liver recovery was compared with wild-type animals.


RESULTS
Gas6 deficiency did not cause any change in CCl(4)-induced liver damage. At 72 h, an efficient tissue repair was observed in wild-type animals whereas in Gas6(-/-) mice, we noticed a defective wound healing accounted by reduced Kupffer cell activation revealed by a decrease in the induction of CD14, TNF-alpha, IL6 and MCP-1. Gas6-deficiency, by limiting cytokine/chemokine release, prevents hepatocyte proliferation, recruitment of circulating monocytes and accumulation of myofibroblasts in healing areas. We also report a direct chemotactic effect of Gas6 on circulating monocytes which might explain defective macrophage infiltration in liver necrotic areas of Gas6(-/-) mice. Interestingly in Gas6(-/-) mice, we observed a high and constitutive expression of Axl and an induction of the suppressor of cytokine signaling SOCS1 after CCl(4) treatment.


CONCLUSIONS
The lower level of cytokines/chemokines in Gas6(-/-) mice after CCl(4) injury, is the consequence of an inhibitory signal arising from Axl receptor overexpression, leading to delayed liver repair in deficient mice.
Lafdil
Fouad
F
INSERM, U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
Chobert
Marie-Noële
MN
Deveaux
Vanessa
V
Zafrani
Elie-Serge
ES
Mavier
Philippe
P
Nakano
Toru
T
Laperche
Yannick
Y
Brouillet
Arthur
A
D000208:Acute Disease; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D016207:Cytokines / Q000096:biosynthesis; D055166:Hepatic Stellate Cells / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D007728:Kupffer Cells / Q000502:physiology; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D015513:Oncogene Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D002251:Carbon Tetrachloride; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6