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Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.: Gas6 deficiency impairs hepatic wound healing

Abstract : BACKGROUND/AIMS: 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.
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Submitted on : Monday, July 20, 2009 - 1:43:33 PM
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Fouad Lafdil, Marie-Noële Chobert, Vanessa Deveaux, Elie-Serge Zafrani, Philippe Mavier, et al.. Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice.: Gas6 deficiency impairs hepatic wound healing. Journal of Hepatology, Elsevier, 2009, 51 (1), pp.55-66. ⟨10.1016/j.jhep.2009.02.030⟩. ⟨inserm-00405375⟩

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