Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages
Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages
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DOI：
10.1128/jvi.00602-20
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发表时间：
2020-09-01
影响因子：
5.4
通讯作者：
An, Jing
中科院分区：
文献类型：
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作者：
Wang, Zhao-Yang;Zhen, Zi-Da;An, Jing
日本脑炎病毒（JEV）是一种引起日本脑炎（JE）的黄病毒，其发病机制尚不清楚。尽管接种了疫苗，每年仍报告有数千人死于乙脑。在这项研究中，我们报告说，缺乏 Axl（一种在黄病毒感染中发挥多种作用的受体酪氨酸激酶）的小鼠在感染 JEV 时表现出更高的死亡率。 Axl 缺陷对 JEV 感染的影响是由血清白细胞介素 1 α (IL-1 α) 水平显着升高介导的，它破坏了血脑屏障，并在感染后 24 小时内促进了病毒的神经侵袭。使用原位感染模型，我们发现死亡的巨噬细胞是观察到的血清 IL-1 α 水平升高的主要来源。 Axl 缺陷通过破坏磷脂酰肌醇 3-激酶 (PI3K)-Akt 信号传导，增强细胞死亡并导致 80% 的 JEV 感染巨噬细胞焦亡。有趣的是，在我们的模型中焦亡巨噬细胞释放的主要效应器是 IL-1 α 而不是 IL-1 β。最后，我们评估了 IL 1 α 拮抗剂的效果，并证明它可以有效预防乙脑的发生。我们的研究结果表明，Axl 在 JEV 感染中发挥保护作用，确定焦亡巨噬细胞释放的 IL-1 α 是促进 JEV 神经侵袭的关键因素，并表明 IL-1 α 拮抗剂可能是 JEV 治疗的候选者。 重要性 日本脑炎病毒 (JEV) 是一种蚊媒黄病毒，可引起日本脑炎 (JE)，这是全世界最常诊断的病毒性脑炎。乙脑的病死率为20%，存活的患者中近一半会出现神经精神后遗症。 Axl 是一种受体酪氨酸激酶，在黄病毒感染中发挥多种作用。目前，Axl 与 JEV 感染的关系仍然是个谜。在这项研究中，我们证明 Axl 通过维持血脑屏障 (BBB) 完整性和限制病毒神经侵袭来阻碍小鼠严重乙型脑炎的发病机制。此外，血清IL-1α是这一过程的关键介质，主要由JEV感染的焦亡巨噬细胞释放以引起BBB破坏，而IL-1α拮抗剂可以有效降低严重乙脑的发病率。我们的工作揭示了 Axl 在对抗严重乙脑中的保护作用，并表明使用 IL-1 α 拮抗剂可能是预防严重乙脑的一种有前途的策略。
Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis. Despite vaccination, thousands of deaths attributed to JE are reported annually. In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection. The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1 alpha (IL-1 alpha) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h postinfection. Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1 alpha levels. Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting phosphatidylinositol 3-kinase (PI3K)-Akt signaling. Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1 alpha rather than IL-1 beta. Finally, we assessed the effect of an IL 1 alpha antagonist and demonstrated that it effectively prevented the incidence of JE. Our results indicate that Axl plays a protective role in JEV infection, identify IL-1 alpha released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1 alpha antagonist may be a candidate for JE therapy.IMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide. The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae. Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections. Currently, the involvement of Axl in JEV infection remains enigmatic. In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion. Furthermore, serum IL-1 alpha is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1 alpha antagonist can effectively reduce the incidence of severe JE. Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of an IL-1 alpha antagonist may be a promising tactic to prevent severe JE.