Alpha/Beta Interferon (IFN-α/β) Signaling in Astrocytes Mediates Protection against Viral Encephalomyelitis and Regulates IFN-γ-Dependent Responses.
Alpha/Beta Interferon (IFN-α/β) Signaling in Astrocytes Mediates Protection against Viral Encephalomyelitis and Regulates IFN-γ-Dependent Responses.
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DOI：
10.1128/jvi.01901-17
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发表时间：
2018-05-15
影响因子：
5.4
通讯作者：
Bergmann CC
中科院分区：
文献类型：
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作者：
Hwang M;Bergmann CC
病毒感染后，不同的中枢神经系统 (CNS) 驻留细胞对保护性 α/β 干扰素 (IFN-α/β) 功能的贡献尚不清楚。基于星形胶质细胞的众多免疫调节功能，我们评估了星形胶质细胞 IFN-α/β 信号传导对预防非致命性胶质细胞和神经营养性小鼠肝炎病毒 (MHV) A59 株的贡献。对与 IFN-α/β 功能相关的基因表达（例如模式识别受体（PRR）和干扰素刺激基因（ISG））的分析表明，脑源性星形胶质细胞的基础 mRNA 水平低于小胶质细胞。尽管星形胶质细胞在感染后很难诱导IFNβ mRNA，但它们比小胶质细胞更高程度地上调IFN-α/β途径中的各种mRNA，支持有效的IFN-α/β反应。使用 mGFAPcre IFNARfl/fl 小鼠消除星形胶质细胞中的 IFN-α/β 受体 (IFNAR) 导致严重的脑脊髓炎和死亡，与不受控制的病毒复制同时发生。此外，尽管中枢神经系统内的 Ifnα/β 和 ISG mRNA 水平持续增加和持续，但病毒传播不仅限于星形胶质细胞，还影响小胶质细胞和神经元。尽管 T 细胞 CNS 浸润减少，但 IFN-γ 是 MHV 控制的关键介质，在受感染的 mGFAPcre IFNARfl/fl 小鼠中并未受损。然而，出乎意料的是，小胶质细胞上 IFN-γ 依赖性主要组织相容性复合物 (MHC) II 类表达的诱导不良表明，缺陷的 IFN-γ 信号传导导致病毒复制失控。持续升高的 IFN-α/β 与 IFN-γ 反应受损之间的联系支持了这样一个新概念：暂时限制早期 IFN-α/β 反应对于有效的抗病毒 IFN-γ 功能至关重要。总的来说，我们的结果表明星形胶质细胞中的 IFN-α/β 信号传导不仅对于限制早期中枢神经系统病毒传播至关重要，而且还促进保护性抗病毒 IFN-γ 功能。重要性 随着适应性免疫的发展，IFN-α/β 建立的抗病毒状态包含最初的病毒传播。虽然中枢神经系统显然缺乏专业的 IFN-α/β 产生者，并且常驻细胞具有引发先天 IFN-α/β 反应的独特能力，但诱导细胞和应答细胞之间的保护性相互作用需要进一步研究。神经胶质细胞和神经元冠状病毒的感染表明，星形胶质细胞对感染的反应比小胶质细胞延迟但更强烈，尽管星形胶质细胞的 IFN-α/β 诱导成分的基础 mRNA 水平较低。星形胶质细胞 IFN-α/β 信号传导消除后致命的、不受控制的病毒传播揭示了单细胞类型中 IFN-α/β 反应对于保护的重要性。与不受控制的病毒相关的持续的整体 IFN-α/β 表达不足以保护神经元，并进一步损害对保护性 IFN-γ 的反应性。结果支持星形胶质细胞是先天免疫的关键贡献者，并且有限的 IFN-α/β 反应对于后续有效的抗病毒 IFN-γ 功能至关重要。
The contribution of distinct central nervous system (CNS) resident cells to protective alpha/beta interferon (IFN-α/β) function following viral infections is poorly understood. Based on numerous immune regulatory functions of astrocytes, we evaluated the contribution of astrocyte IFN-α/β signaling toward protection against the nonlethal glia- and neuronotropic mouse hepatitis virus (MHV) strain A59. Analysis of gene expression associated with IFN-α/β function, e.g., pattern recognition receptors (PRRs) and interferon-stimulated genes (ISGs), revealed lower basal mRNA levels in brain-derived astrocytes than in microglia. Although astrocytes poorly induced Ifnβ mRNA following infection, they upregulated various mRNAs in the IFN-α/β pathway to a higher extent than microglia, supporting effective IFN-α/β responsiveness. Ablation of the IFN-α/β receptor (IFNAR) in astrocytes using mGFAPcre IFNARfl/fl mice resulted in severe encephalomyelitis and mortality, coincident with uncontrolled virus replication. Further, virus spread was not restricted to astrocytes but also affected microglia and neurons, despite increased and sustained Ifnα/β and ISG mRNA levels within the CNS. IFN-γ, a crucial mediator for MHV control, was not impaired in infected mGFAPcre IFNARfl/fl mice despite reduced T cell CNS infiltration. Unexpectedly however, poor induction of IFN-γ-dependent major histocompatibility complex (MHC) class II expression on microglia supported that defective IFN-γ signaling contributes to uncontrolled virus replication. A link between sustained elevated IFN-α/β and impaired responsiveness to IFN-γ supports the novel concept that temporally limited early IFN-α/β responses are critical for effective antiviral IFN-γ function. Overall, our results imply that IFN-α/β signaling in astrocytes is not only critical in limiting early CNS viral spread but also promotes protective antiviral IFN-γ function. IMPORTANCE An antiviral state established by IFN-α/β contains initial viral spread as adaptive immunity develops. While it is apparent that the CNS lacks professional IFN-α/β producers and that resident cells have distinct abilities to elicit innate IFN-α/β responses, protective interactions between inducer and responder cells require further investigation. Infection with a glia- and neuronotropic coronavirus demonstrates that astrocytes mount a delayed but more robust response to infection than microglia, despite their lower basal mRNA levels of IFN-α/β-inducing components. Lethal, uncontrolled viral dissemination following ablation of astrocyte IFN-α/β signaling revealed the importance of IFN-α/β responses in a single cell type for protection. Sustained global IFN-α/β expression associated with uncontrolled virus did not suffice to protect neurons and further impaired responsiveness to protective IFN-γ. The results support astrocytes as critical contributors to innate immunity and the concept that limited IFN-α/β responses are critical for effective subsequent antiviral IFN-γ function.