Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice
Growth arrest-specific protein 6 deficiency impairs liver tissue repair after acute toxic hepatitis in mice
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DOI：
10.1016/j.jhep.2009.02.030
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发表时间：
2009-07-01
影响因子：
25.7
通讯作者：
Brouillet, Arthur
中科院分区：
文献类型：
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作者：
Lafdil, Fouad;Chobert, Marie-Noele;Brouillet, Arthur
背景/目的：源自肝星状细胞的常驻巨噬细胞和肌成纤维细胞在肝脏伤口愈合中发挥关键作用。我们之前报道过这些正弦细胞分泌生长停滞特异性蛋白 6 (Gas6) 并表达 Axl（其受体之一）。在此，我们探讨Gas6在急性肝损伤愈合过程中的作用。方法：在Gas6缺陷（Gas6（-/-））小鼠中注射一次四氯化碳诱导中毒性肝炎，并将肝脏恢复情况与野生型动物进行比较。结果：Gas6缺陷不会引起CCl4诱导的肝损伤的任何变化。 72小时时，在野生型动物中观察到有效的组织修复，而在Gas6(-/-)小鼠中，我们注意到伤口愈合有缺陷，这是由于库普弗细胞活化减少所致，CD14、TNF-α、IL6和MCP-1的诱导减少揭示了这一点。 Gas6 缺乏通过限制细胞因子/趋化因子的释放，阻止肝细胞增殖、循环单核细胞的募集以及愈合区域肌成纤维细胞的积累。我们还报告了 Gas6 对循环单核细胞的直接趋化作用，这可能解释了 Gas6(-/-) 小鼠肝坏死区域中巨噬细胞浸润缺陷的原因。有趣的是，在 Gas6(-/-) 小鼠中，我们观察到 CCl4 处理后 Axl 的高组成型表达以及细胞因子信号转导抑制剂 SOCS1 的诱导。结论：CCl4 损伤后 Gas6(-/-) 小鼠中细胞因子/趋化因子水平较低，是 Axl 受体过度表达产生的抑制信号的结果，导致缺陷小鼠的肝脏修复延迟。 (C) 2009 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
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 CCl4-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 CCl4 treatment.Conclusions: The lower level of cytokines/chemokines in Gas6(-/-) mice after CCl4 injury, is the consequence of an inhibitory signal arising from Axl receptor overexpression, leading to delayed liver repair in deficient mice. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.