Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli
Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli
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DOI：
10.1002/glia.20450
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发表时间：
2007-02-01
期刊：
影响因子：
6.2
通讯作者：
Miller, Stephen D.
中科院分区：
文献类型：
--
作者：
Carpentier, Pamela A.;Williams, Bryan R.;Miller, Stephen D.
受损的免疫监视和本构性免疫抑制特性使中枢神经系统（CNS）成为免疫防御的一个特殊挑战，并要求中枢神经系统驻留细胞能够快速识别和响应感染。我们之前已经表明，星形胶质细胞对TLR3配体poly I:C的治疗有反应，先天免疫功能上调。在当前的研究中，我们研究了星形胶质细胞先天免疫功能被Theiler小鼠脑脊髓炎病毒（TMEV）激活的情况，TMEV是一种小病毒，它在易感小鼠的中枢神经系统中建立了持续感染，并导致类似于人类多发性硬化症的自身免疫性脱髓鞘疾病的发展。被TMEV感染的星形细胞被激活产生I型干扰素、细胞因子IL-6和趋化因子CCL2和CXCL10。我们进一步研究了在直接病毒感染和poly I:C治疗下星形胶质细胞激活的机制。我们发现细胞质dsrna激活的激酶PKR对TMEV感染的先天免疫应答很重要，但在细胞外传递的poly I:C诱导中没有作用。相比之下，我们发现TLR3在对TMEV感染的反应中仅起次要作用，但在对poly I:C的反应中很重要。这些结果突出了直接非溶性病毒感染和细胞外多聚I:C诱导的应答之间的差异。星形胶质细胞通过这些不同途径的激活与病毒性脑炎和脱髓鞘疾病（如多发性硬化症）的发生和发展有关。(c) 2006 Wiley-Liss, Inc。
Impaired immune surveillance and constitutive immunosuppressive properties make the central nervous system (CNS) a particular challenge to immune defense, and require that CNS-resident cells be capable of rapidly recognizing and responding to infection. We have previously shown that astrocytes respond to treatment with a TLR3 ligand, poly I:C, with the upregulation of innate immune functions. In the current study, we examine the activation of innate immune functions of astrocytes by Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, which establishes a persistent infection in the CNS of susceptible strains of mice and leads to the development of an autoimmune demyelinating disease that resembles human multiple sclerosis. Astrocytes infected with TMEV are activated to produce type I interferons, the cytokine IL-6, and chemokines CCL2 and CXCL10. We further examined the mechanisms that are responsible for the activation of astrocytes in response to direct viral infection and treatment with poly I:C. We found that the cytoplasmic dsRNA-activated kinase PKR is important for innate immune responses to TMEV infection, but has no role in their induction by poly I:C delivered extracellularly. In contrast, we found that TLR3 has only a minor role in responses to TMEV infection, but is important for responses to poly I:C. These results highlight the differences between responses induced by direct, nonlytic virus infection and extracellular poly I:C. The activation of astrocytes through these different pathways has implications for the initiation and progression of viral encephalitis and demyelinating diseases such as multiple sclerosis. (c) 2006 Wiley-Liss, Inc.