Lafdil Fouad, Chobert Marie-Noële, Deveaux Vanessa, Zafrani Elie-Serge, Mavier Philippe, Nakano Toru, Laperche Yannick, Brouillet Arthur
INSERM, U955, Institut Mondor de Recherche Biomédicale, 94010 Créteil, France.
J Hepatol. 2009 Jul;51(1):55-66. doi: 10.1016/j.jhep.2009.02.030. Epub 2009 Apr 22.
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.
Toxic hepatitis was induced by a single carbon tetrachloride injection in Gas6 deficient (Gas6(-/-)) mice and liver recovery was compared with wild-type animals.
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.
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.
背景/目的：源自肝星状细胞的驻留巨噬细胞和成肌纤维细胞在肝脏伤口愈合中起关键作用。我们之前报道过这些窦状细胞分泌生长停滞特异性蛋白6（Gas6）并表达其受体之一Axl。在此我们探讨Gas6在急性肝损伤愈合过程中的作用。
通过单次注射四氯化碳诱导Gas6缺陷（Gas6(-/-)）小鼠发生中毒性肝炎，并将肝脏恢复情况与野生型动物进行比较。
Gas6缺陷并未导致四氯化碳诱导的肝损伤出现任何变化。在72小时时，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存在缺陷，这是由于库普弗细胞活化减少所致，表现为CD14、肿瘤坏死因子-α、白细胞介素6和单核细胞趋化蛋白-1诱导水平降低。Gas6缺陷通过限制细胞因子/趋化因子释放，阻止肝细胞增殖、循环单核细胞募集以及成肌纤维细胞在愈合区域的积聚。我们还报道了Gas6对循环单核细胞具有直接趋化作用，这可能解释了Gas6(-/-)小鼠肝脏坏死区域巨噬细胞浸润存在缺陷的原因。有趣的是，在Gas6(-/-)小鼠中，我们观察到Axl的高组成性表达以及四氯化碳处理后细胞因子信号转导抑制因子SOCS1的诱导表达。
四氯化碳损伤后Gas6(-/-)小鼠中细胞因子/趋化因子水平较低，是Axl受体过表达产生的抑制信号所致，导致缺陷小鼠肝脏修复延迟。
