C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis
C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis
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NLRP3 炎性体和 IL-1β 加速实验性病毒性暴发性肝炎中免疫介导的病理学。
DOI：
10.1016/j.jhep.2014.08.050
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发表时间：
2015-02-01
影响因子：
25.7
通讯作者：
Guo, Bo
中科院分区：
文献类型：
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作者：
Liu, Jianjun;Tan, Yulong;Guo, Bo
背景与目的：病毒性暴发性肝炎（FH）是一种死亡率很高的疾病。补体系统的激活与FH的发生有关。然而，在FH中介导补体激活的关键因素仍然难以捉摸。方法：分别从乙型肝炎病毒（HBV）感染的FH患者和小鼠肝炎病毒3株（MHV-3）感染的小鼠中分离肝组织。野生型小鼠用或不加C5aR或Tnf - α拮抗剂治疗，C5aR（C5aR(-/-)）、Fgl2（Fgl2(-/-)）和Tnf - α (Tnf -(-/-))缺失小鼠不用拮抗剂治疗。通过免疫组织化学、免疫荧光或ELISA检测C5b-9、C5aR、FGL2、CD31、CD11b、纤维蛋白、tnf - α和补体C3切割产物。体外用C5a、tnf - α或MHV-3刺激分选的肝窦内皮细胞（LSECs）或骨髓源性（CD11b(+)）细胞。qRT-PCR检测Fgl2、Tnf α mRNA表达水平。结果：我们观察到，补体激活、凝血和促炎细胞因子的产生在HBV+ FH患者中上调。在小鼠FH模型中也进行了类似的观察。在缺乏C5aR、Tnfa或Fgl2的情况下，MHV-3感染小鼠的补体活化和凝血功能显著降低。MHV-3感染的C5aR（-/-）小鼠表现出浸润炎性CD11b（+）细胞数量减少，tnf - α和FGL2表达减少。此外，C5a刺激CD11b（+）细胞产生tnf - α，进而促进体外CD31(+) lsec样细胞中FGL2的表达。C5aR或tnf - α拮抗剂可改善mhv -3诱导的FH。结论：我们的研究结果表明，C5aR、tnf - α和FGL2形成了一个完整的网络，有助于凝血和补体激活，并表明它们是病毒FH干预的潜在治疗靶点。(C) 2014欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: Viral fulminant hepatitis (FH) is a disease with a high mortality rate. Activation of the complement system correlates with the development of FH. However, the key factors mediating complement activation in FH remain elusive.Methods: Liver tissues were isolated from FH patients infected by hepatitis B virus (HBV) and from mice infected with murine hepatitis virus strain 3 (MHV-3). Wild type mice were treated with or without antagonists of C5aR or TNF-alpha, and mice deficient for C5aR (C5aR(-/-)), Fgl2 (Fgl2(-/-)), and Tnf alpha (Tnf alpha(-/-)) mice were not treated with the antagonists. C5b-9, C5aR, FGL2, CD31, CD11b, fibrin, TNF-alpha, and complement C3 cleavage products were detected by immunohistochemistry, immunofluorescence, or ELISA. Sorted liver sinusoidal endothelial cells (LSECs) or myeloid-derived (CD11b(+)) cells were stimulated with C5a, TNF-alpha or MHV-3 in vitro. The mRNA expressions levels of Fgl2 and Tnf alpha were determined by qRT-PCR analyses.Results: We observed that complement activation, coagulation and pro-inflammatory cytokine production were upregulated in the HBV+ patients with FH. Similar observations were made in the murine FH models. Complement activation and coagulation were significantly reduced in MHV-3 infected mice in the absence of C5aR, Tnfa or Fgl2. The MHV-3 infected C5aR(-/-) mice exhibited reduced numbers of infiltrated inflammatory CD11b(+) cells and a reduced expression of TNF-alpha and FGL2. Moreover, C5a administration stimulated TNF-alpha production by CD11b(+) cells, which in turn promoted the expression of FGL2 in CD31(+) LSEC-like cells in vitro. Administration of antagonists against C5aR or TNF-alpha ameliorated MHV-3-induced FH.Conclusions: Our results demonstrate that C5aR, TNF-alpha, and FGL2 form an integral network that contributes to coagulation and complement activation, and suggest that those are potential therapeutic targets in viral FH intervention. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.