Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil-mediated complement activation.
Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil-mediated complement activation.
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巨噬细胞清道夫受体1通过中性粒细胞介导的补体激活促进暴发性肝炎的发病机制
DOI：
10.1016/j.jhep.2017.11.010
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发表时间：
2018-04
影响因子：
25.7
通讯作者：
Zuo D
中科院分区：
文献类型：
--
作者：
Tang Y;Li H;Li J;Liu Y;Li Y;Zhou J;Zhou J;Lu X;Zhao W;Hou J;Wang XY;Chen Z;Zuo D
巨噬细胞清道夫受体1（macrophage scavenger receptor 1，Msr 1，SRA）是一种主要表达于骨髓细胞的模式识别受体，在维持免疫稳态中发挥重要作用。由于MSR 1在重型肝炎（FH）患者肝脏中表达上调，我们研究了MSR 1在FH发病机制中的作用机制。用小鼠肝炎病毒A59株（MHV-A59）感染Msr 1-缺陷型（Msr 1-/-）小鼠及其野生型（WT）同窝仔，诱导FH，并测定和比较组织损伤、血清丙氨酸氨基转移酶、炎性细胞因子和补体成分5a（C5 a）水平。研究了MHV感染后伴或不伴中性粒细胞耗竭的肝损伤。我们的研究结果表明，Msr 1 −/−小鼠对MHV诱导的肝炎具有抵抗力。用C5 a受体拮抗剂（C5 aRa）治疗减少了MHV感染的野生型和Msr 1 −/−小鼠之间炎症反应和肝损伤的差异，表明C5 a诱导的促炎反应在Msr 1介导的FH发病机制调节中起着关键作用。我们证明，Msr 1有效地增强转化生长因子激活的激酶-1的磷酸化中性粒细胞MHV-A59刺激后，从而促进细胞外信号调节激酶途径的激活和随后NETosis的形成。此外，我们提供的证据表明，Msr 1的阻断减弱了MHV-A59感染引起的肝损伤。Msr 1通过增强中性粒细胞NETosis的诱导和随后的补体激活促进病毒诱导的FH的发病机制。以Msr 1为靶点可能成为治疗FH的一种新的免疫策略。病毒性暴发性肝炎（FH）是一种世界范围内死亡率很高的疾病。FH患者和小鼠实验性FH的肝脏中巨噬细胞清道夫受体1（Msr 1）的水平增强，表明Msr 1在FH的发病机制中起作用。在此，我们证明了Msr 1缺陷的小鼠对MHV-A59诱导的FH具有抗性，并且Msr 1抑制剂岩藻依聚糖抑制小鼠FH的进展。我们的研究表明，使用抑制MSR 1功能的药物可能对FH患者有益。
The macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, which plays an important role in the maintenance of immune homeostasis. Since MSR1 expression was upregulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 in FH pathogenesis. Msr1-deficient (Msr1−/−) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase, inflammatory cytokines and complement component 5a (C5a) were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion. Our results showed that Msr1−/− mice were resistant to MHV-induced hepatitis. Treatment with the C5a receptor antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected wild-type and Msr1−/− mice, suggesting that C5a-induced proinflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced transforming growth factor-activated kinase-1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of the extracellular signal-regulated kinase pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection. Msr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and subsequent complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH. Virus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced levels of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 plays a role in the pathogenesis of FH. Herein, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH.
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A类清除受体1（MSR1）通过介导类似Toll样受体3识别相邻细胞中产生的病毒RNA的识别来限制丙型肝炎病毒复制。
影响因子：
6.7
作者：
Dansako H;Yamane D;Welsch C;McGivern DR;Hu F;Kato N;Lemon SM
通讯作者：
Lemon SM
影响因子：
--
作者：
Baer MT;Huang N;Gibson FC 3rd
通讯作者：
Gibson FC 3rd
影响因子：
5.4
作者：
Cheng, Shih-Chin;Sprong, Tom;Netea, Mihai G.
通讯作者：
Netea, Mihai G.
影响因子：
8.7
作者：
Liao, HS;Kodama, T;Geng, YJ
通讯作者：
Geng, YJ
DOI：
10.4049/jimmunol.1201719
发表时间：
2012-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kaplan MJ;Radic M
通讯作者：
Radic M