Steffensen Maria Abildgaard, Fenger Christina, Christensen Jeanette Erbo, Jørgensen Carina Krogsgaard, Bassi Maria Rosaria, Christensen Jan Pravsgaard, Finsen Bente, Thomsen Allan Randrup
Department of International Health, Immunology, and Microbiology, University of Copenhagen, Copenhagen, Denmark.
Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
J Virol. 2014 Dec;88(24):14090-104. doi: 10.1128/JVI.01346-14. Epub 2014 Sep 24.
Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-γ) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i., but in this model, the upregulation was only partially dependent on IFN-γ and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation.
In the present report, we have studied the induction of SOCS1 and SOCS3 expression in the context of virus-induced CNS infection. We found that both a noncytolytic and a cytolytic virus induce marked upregulation of SOCS1 and -3 expression. Notably, the kinetics of the observed upregulation follows that of activity within proinflammatory signaling pathways and, interestingly, type II interferon (IFN), which is also a key inducer of inflammatory mediators, seems to be essential in initiating this counterinflammatory response. Another key observation is that not only cells of the immune system but also CNS resident cells are actively involved in both the pro- and the counterinflammatory immune circuits; thus, for example, astrocytes upregulate both C-X-C-motif chemokine 10 (CXCL10) and SOCS when exposed to type II IFN in vivo.
细胞因子信号转导抑制因子（SOCS）蛋白是细胞内蛋白，可在多种细胞类型中抑制细胞因子信号转导。许多病毒感染与SOCS上调有关；然而，关于病毒感染期间调节SOCS表达的机制知之甚少。在本研究中，我们使用两种病理特征不同的脑内（i.c.）感染模型来表征病毒感染的中枢神经系统（CNS）中SOCS表达的时间和空间方面，并通过使用各种基因敲除小鼠模型，我们试图确定可能是病毒诱导CNS中SOCS上调基础的调节机制。我们发现，脑内感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）或黄热病毒（YF）均导致SOCS1/3 mRNA表达逐渐上调，在感染后第7天（p.i.）达到峰值。在LCMV模型中，SOCS mRNA在脑内驻留细胞中表达，包括星形胶质细胞和一些神经元，特别是对于SOCS1，这种上调几乎完全由浸润的T细胞产生的γ干扰素（IFN-γ）介导。感染YF后，我们还发现脑内驻留细胞中SOCS表达上调，在感染后第7天达到峰值，但在该模型中，上调仅部分依赖于IFN-γ和T细胞，这表明至少还有一种其他介质参与YF感染后SOCS的上调。我们得出结论，病毒诱导的CNS炎症与脑内驻留细胞中SOCS1/3 mRNA表达上调有关，并且至少有两条不同的途径可导致这种上调。
在本报告中，我们研究了病毒诱导的CNS感染情况下SOCS1和SOCS3表达的诱导情况。我们发现，非溶细胞性和溶细胞性病毒均诱导SOCS1和-3表达显著上调。值得注意的是，观察到的上调动力学与促炎信号通路中的活性动力学一致，有趣的是，II型干扰素（IFN）也是炎症介质的关键诱导物，似乎在启动这种抗炎反应中至关重要。另一个关键观察结果是，不仅免疫系统的细胞，而且CNS驻留细胞都积极参与促炎和抗炎免疫回路；因此，例如，星形胶质细胞在体内暴露于II型IFN时会上调C-X-C基序趋化因子10（CXCL10）和SOCS。
