C5a/C5aR Pathway Is Essential for the Pathogenesis of Murine Viral Fulminant Hepatitis by Way of Potentiating Fgl2/Fibroleukin Expression
C5a/C5aR Pathway Is Essential for the Pathogenesis of Murine Viral Fulminant Hepatitis by Way of Potentiating Fgl2/Fibroleukin Expression
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C5a/C5aR 途径通过增强 Fgl2/纤维白介素表达对于鼠病毒性暴发性肝炎的发病机制至关重要
DOI：
10.1002/hep.27114
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发表时间：
2014-07-01
期刊：
影响因子：
13.5
通讯作者：
Wu, Yu-zhang
中科院分区：
文献类型：
--
作者：
Xu, Gui-lian;Chen, Jian;Wu, Yu-zhang
病毒性暴发性肝炎（FH）仍然是一个严重的临床问题，死亡率非常高。缺乏对FH发病机制的理解实质上阻碍了有效的临床治疗。从补体成分5（C5）的遗传差异和小鼠品系对小鼠肝炎病毒株-3（MHV-3）感染的易感性之间观察到的相关性推断，我们提出过度的补体激活在FH的发展中起着关键作用。我们发现MHV-3感染引起大量补体激活，沿着血清C5 a水平的快速升高和易感株FH的快速发展。C5 a受体（C5 aR）缺陷的小鼠或用C5 aR拮抗剂（C5 aRa）处理的易感品系表现出疾病的显著减弱，伴随着肝纤维蛋白原样蛋白2（Fgl 2）的显著减少，所述肝纤维蛋白原样蛋白2是引起感染的肝脏坏死的标志性蛋白。因此，FH患者的活检显示Fgl 2表达的显著增加，其与肝脏中的C5 aR上调相关。体外C5 a施用加速MHV-3诱导的巨噬细胞的Fgl 2分泌。此外，在病毒感染期间，抑制ERK 1/2和p38有效地阻断C5 a介导的Fgl 2产生。结论：这些数据提供的证据表明，小鼠对MHV-3诱导的FH的易感性可能依赖于C5 a/C5 aR相互作用，ERK 1/2和p38通路参与上调Fgl 2表达。预期抑制C5 a/C5 aR相互作用在FH患者的临床治疗中是有益的。
Viral fulminant hepatitis (FH) remains a serious clinical problem with very high mortality. Lacking understanding of FH pathogenesis has in essence hindered efficient clinical treatment. Inferring from a correlation observed between the genetic differences in the complement component 5 (C5) and the susceptibility of mouse strains to murine hepatitis virus strain-3 (MHV-3) infections, we propose that excessive complement activation plays a critical role in the development of FH. We show that MHV-3 infection causes massive complement activation, along with a rapid increase in serum C5a levels and quick development of FH in susceptible strains. Mice deficient in the C5a receptor (C5aR) or the susceptible strains treated with C5aR antagonists (C5aRa) exhibit significant attenuation of the disease, accompanied by a remarkable reduction of hepatic fibrinogen-like protein 2 (Fgl2), a hallmark protein that causes necrosis of infected livers. In accordance, biopsy of FH patients shows a dramatic increase of Fgl2 expression, which correlates with C5aR up-regulation in the liver. In vitro C5a administration accelerates MHV-3-induced Fgl2 secretion by macrophages. Furthermore, inhibiting ERK1/2 and p38 efficiently blocks C5a-mediated Fgl2 production during viral infections. Conclusion: These data provide evidence that mouse susceptibility to MHV-3-induced FH may rely on C5a/C5aR interactions, for which ERK1/2 and p38 pathways participate in up-regulating Fgl2 expression. Inhibition of C5a/C5aR interactions is expected to be beneficial in the clinical treatment of FH patients.