The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis.
The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis.
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DOI：
10.1371/journal.ppat.1005155
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发表时间：
2015-09
期刊：
影响因子：
6.7
通讯作者：
Chen Y
中科院分区：
文献类型：
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作者：
Guo S;Yang C;Diao B;Huang X;Jin M;Chen L;Yan W;Ning Q;Zheng L;Wu Y;Chen Y
病毒性暴发性肝炎（FH）是一种严重的疾病，死亡率高，导致感染的肝脏过度炎症。由于缺乏对病毒感染肝脏炎症发病机制的认识，临床干预措施一直效率低下。我们发现，野生型小鼠感染鼠肝炎病毒株-3（MHV-3），病毒FH模型，表现出严重的疾病和高死亡率，与血清和肝脏中IL-1β表达的显著升高相关。然而，在IL-1β受体-I缺陷（IL-1 R1-/-）或IL-1 R拮抗剂（IL-1 Ra）处理的小鼠中的病毒感染显示病毒复制、疾病进展和死亡率降低。IL-1 R1缺乏似乎削弱了病毒诱导的巨噬细胞中纤维蛋白原样蛋白-2（FGL 2）的产生和肝脏中CD 45 +Gr-1high中性粒细胞浸润。受感染的巨噬细胞快速释放活性氧（ROS）表明NLRP 3炎性小体激活的合理病毒启动。进一步的实验表明，缺乏p47 phox（一种控制急性ROS产生的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基）的小鼠在病毒感染期间表现出NLRP 3炎性小体活化和随后的IL-1β分泌的减少，这似乎是获得对病毒FH的恢复力的原因。此外，NLRP 3和Caspase-1（炎性小体复合物的两种基本组分）缺陷的病毒感染动物也具有降低的IL-1β诱导沿着改善的肝炎。我们的研究结果表明，ROS/NLRP 3/IL-1β轴是病毒感染过程中过度激活并直接导致严重肝脏疾病的重要信号通路，这为开发人类病毒性FH和其他严重炎症性疾病的有效治疗方法提供了启示。NLRP 3炎性体和IL-1β在介导宿主对病原体入侵的初级炎症反应中起重要作用。在某些情况下，这种信号通路的过度激活可能导致危及生命的疾病。然而，尚不清楚NLRP 3炎性体活化是否参与病毒性暴发性肝炎（FH）的发病机制，病毒性暴发性肝炎是一种临床严重综合征，其特征在于肝脏中的急性炎症沿着肝细胞的大量坏死和病毒感染期间的肝性脑病。使用小鼠肝炎病毒株-3（MHV-3）感染的小鼠病毒FH模型，我们观察到显着的巨噬细胞诱导以及血清和肝脏中IL-1β的大量积聚。相反，IL-1β信号的中断导致MHV-3诱导的肝炎和死亡率的减弱。阻断IL-1β活性可降低病毒诱导的巨噬细胞纤维蛋白原样蛋白-2（FGL 2）表达，并限制病毒感染后CD 45 +Gr-1high中性粒细胞在肝脏的募集。我们进一步表明，proIL-1β是由NLRP 3炎性体生物加工。炎性小体复合物中的组分（包括NLRP 3和半胱天冬酶-1）的缺失导致病毒诱导的IL-1β产生的减少和疾病进展的减轻。进一步的研究表明，缺乏烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基p47 phox（一种控制急性ROS产生的蛋白质）的巨噬细胞阻止NLRP 3炎性小体激活和IL-1β分泌，表明病毒诱导的ROS产生可直接启动NLRP 3炎性小体激活。因此，p47 phox-/-小鼠表现出一定程度的MHV-3抗性。综上所述，这些结果表明，ROS/NLRP 3/IL-1β是导致小鼠病毒FH的炎症反应加剧的关键信号通路，表明该信号级联的介导可能有利于疾病治疗。
Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Whereas, the viral infection in IL-1β receptor-I deficient (IL-1R1 -/-) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45+Gr-1high neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47 phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1β induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1β axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases. The NLRP3 inflammasome and IL-1β play essential roles in mediating the primary inflammatory responses against pathogen invasions in the host. Hyperactivation of this signaling pathway can lead to life-threatening diseases under certain circumstances. However, it is not clear if NLRP3 inflammasome activation participates in the pathogenesis of viral fulminant hepatitis (FH), a clinical severe syndrome characterized by acute inflammation in the liver along with massive necrosis of hepatocytes and hepatic encephalopathy during viral infection. Using a mouse viral FH model by infection with murine hepatitis virus strain-3 (MHV-3), we observed a significant macrophage induction and the serum and liver massive accumulation of IL-1β. Conversely, interruption of IL-1β signals results in attenuation of the MHV-3-induced hepatitis and mortality. Blocking IL-1β activity reduces the virus-induced expression of fibrinogen-like protein-2 (FGL2) in macrophages, and limits the liver recruitment of CD45+Gr-1high neutrophils upon the virus infection. We further show that proIL-1β is bioprocessed by NLRP3 inflammasome. Deletion of the components in the inflammasome complex, including NLRP3 and Caspase-1, leads to reduction in the virus-induced IL-1β production and lessening of disease progression. Further studies show that macrophages in deficiency of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47 phox, a protein that controls acute ROS production, prevents NLRP3 inflammasome activation and IL-1β secretion, suggesting that the virus-induced ROS production can directly initiate NLRP3 inflammasome activation. Therefore, p47 phox-/- mice exhibited certain degrees of MHV-3 resistance. Taken together, these results demonstrate that ROS/NLRP3/IL-1β is the key pathway signaling exacerbated inflammatory responses that cause viral FH in mice, suggesting that mediation of this signal cascade may benefit on the disease treatment.