Type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice.
Type-1 angiotensin receptor signaling in central nervous system myeloid cells is pathogenic during fatal alphavirus encephalitis in mice.
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DOI：
10.1186/s12974-016-0683-7
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发表时间：
2016-08-25
影响因子：
9.3
通讯作者：
Irani DN
中科院分区：
文献类型：
--
作者：
Blakely PK;Huber AK;Irani DN
甲病毒可导致人类致命性脑炎。自然感染通过受感染蚊子的叮咬发生，但气溶胶传播性使其中一些病毒成为潜在的生物恐怖主义制剂。中枢神经系统（CNS）宿主反应有助于实验模型中甲病毒的发病机制，是合理的治疗靶点。我们研究了中枢神经系统内烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）活性产生的活性氧（ROS）是否会导致小鼠致命性甲病毒脑炎。考虑到血管紧张素受体阻断剂替米沙坦能够穿过血脑屏障，选择性阻断1型血管紧张素受体（AT 1 R），并抑制血管平滑肌和其他神经组织中的Nox源性ROS产生，因此对感染动物进行全身性治疗。临床、病毒学、生物化学和组织病理学结果随时间进行随访。血管紧张素II（Ang II）/AT 1 R轴在疾病发病机制中的重要性得到了证实，证明感染后CNS中Ang II水平升高，CNS Ang II产生受到抑制时疾病存活率提高，小胶质细胞和组织浸润性骨髓细胞上AT 1 R表达增加，AT 1 R缺陷小鼠与野生型（WT）对照组相比疾病存活率提高。替米沙坦全身给药以剂量依赖性方式保护WT小鼠免受两种不同甲病毒引起的致死性脑炎，而不改变病毒复制或在CNS中发挥任何抗炎作用。感染引起CNS中多个Nox亚基的上调，而药物治疗抑制局部Nox活性、ROS产生和氧化性神经元损伤。替米沙坦在Nox缺陷小鼠中被证明是无效的，表明这种酶是其在该实验环境中的主要靶标。Nox衍生的ROS，可能由AT 1 R信号触发的CNS髓样细胞产生，在小鼠致命性甲病毒脑炎期间是致病性的。非膨胀剂量的替米沙坦全身给药靶向CNS中的Nox活性，以发挥神经保护作用。该途径的破坏可能对相关感染的治疗以及由氧化损伤驱动的其他CNS疾病具有更广泛的意义。本文的在线版本（doi：10.1186/s12974-016-0683-7）包含补充材料，可供授权用户使用。
Alphaviruses can cause fatal encephalitis in humans. Natural infections occur via the bite of infected mosquitos, but aerosol transmissibility makes some of these viruses potential bioterrorism agents. Central nervous system (CNS) host responses contribute to alphavirus pathogenesis in experimental models and are logical therapeutic targets. We investigated whether reactive oxygen species (ROS) generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity within the CNS contributes to fatal alphavirus encephalitis in mice. Infected animals were treated systemically with the angiotensin receptor-blocking drug, telmisartan, given its ability to cross the blood-brain barrier, selectively block type-1 angiotensin receptors (AT1R), and inhibit Nox-derived ROS production in vascular smooth muscle and other extraneural tissues. Clinical, virological, biochemical, and histopathological outcomes were followed over time. The importance of the angiotensin II (Ang II)/AT1R axis in disease pathogenesis was confirmed by demonstrating increased Ang II levels in the CNS following infection, enhanced disease survival when CNS Ang II production was suppressed, increased AT1R expression on microglia and tissue-infiltrating myeloid cells, and enhanced disease survival in AT1R-deficient mice compared to wild-type (WT) controls. Systemic administration of telmisartan protected WT mice from lethal encephalitis caused by two different alphaviruses in a dose-dependent manner without altering virus replication or exerting any anti-inflammatory effects in the CNS. Infection triggered up-regulation of multiple Nox subunits in the CNS, while drug treatment inhibited local Nox activity, ROS production, and oxidative neuronal damage. Telmisartan proved ineffective in Nox-deficient mice, demonstrating that this enzyme is its main target in this experimental setting. Nox-derived ROS, likely arising from CNS myeloid cells triggered by AT1R signaling, are pathogenic during fatal alphavirus encephalitis in mice. Systemically administered telmisartan at non-hypotensive doses targets Nox activity in the CNS to exert a neuroprotective effect. Disruption of this pathway may have broader implications for the treatment of related infections as well as for other CNS diseases driven by oxidative injury. The online version of this article (doi:10.1186/s12974-016-0683-7) contains supplementary material, which is available to authorized users.
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影响因子：
3.3
作者：
Gonzalez, A. D.;Wang, G.;Waters, E. M.;Gonzales, K. L.;Speth, R. C.;Van Kempen, T. A.;Marques-Lopes, J.;Young, C. N.;Butler, S. D.;Davisson, R. L.;Iadecola, C.;Pickel, V. M.;Pierce, J. P.;Milner, T. A.
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影响因子：
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影响因子：
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影响因子：
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作者：
Jung, S;Aliberti, J;Littman, DR
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Littman, DR