Peripheral inflammatory stimuli increase proinflammatory cytokines in the bloodstream and central nervous system and activate microglial cells. Here we tested the hypothesis that contrasting environments mimicking sedentary and active lives would be associated with differential microglial morphological responses, inflammatory cytokines concentration, and virus load in the peripheral blood. For this, mice were maintained either in standard (standard environment) or enriched cages (enriched environment) and then subjected to a single (DENV1) serotype infection. Blood samples from infected animals showed higher viral loads and higher tumor necrosis factor-α (TNFα) mRNA concentrations than control subjects. Using an unbiased stereological sampling approach, we selected 544 microglia from lateral septum for microscopic 3D reconstruction. Morphological complexity contributed most to cluster formation. Infected groups exhibited significant increase in the microglia morphological complexity and number, despite the absence of dengue virus antigens in the brain. Two microglial phenotypes (type I with lower and type II with higher morphological complexity) were found in both infected and control groups. However, microglia from infected mice maintained in enriched environment showed only one morphological phenotype. Two-way ANOVA revealed that environmental changes and infection influenced type-I and II microglial morphologies and number. Environmental enrichment and infection interactions may contribute to microglial morphological change to a point that type-I and II morphological phenotypes could no longer be distinguished in infected mice from enriched environment. Significant linear correlation was found between morphological complexity and TNFα peripheral blood. Our findings demonstrated that sedentary-like and active murine models exhibited differential microglial responses and peripheral inflammation to systemic non-neurotropic infections with DENV1 virus.

中文翻译：

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全身性非神经营养性登革热病毒感染后久坐样和活跃鼠模型的微胶质细胞形态反应，TNFα和病毒载量的差异。

周围炎性刺激增加血液和中枢神经系统中的促炎细胞因子并激活小胶质细胞。在这里，我们测试了这样一种假说，即模仿久坐和活跃生活的对比环境可能与微胶质细胞形态反应，炎症性细胞因子浓度和外周血中的病毒载量有关。为此，将小鼠维持在标准（标准环境）或富集笼子（富集环境）中，然后进行单一（DENV1）血清型感染。与对照组相比，感染动物的血液样本显示出更高的病毒载量和更高的肿瘤坏死因子-α（TNFα）mRNA浓度。使用无偏立体采样方法，我们从侧隔中选择了544个小胶质细胞进行微观3D重建。形态复杂性是导致簇形成的最大原因。尽管脑中不存在登革热病毒抗原，但感染组的小胶质细胞形态复杂性和数量显着增加。在感染组和对照组中均发现了两种小胶质细胞表型（I型较低，II型具有较高的形态复杂性）。然而，在富集环境中维持的感染小鼠的小胶质细胞仅表现出一种形态表型。双向方差分析表明，环境变化和感染会影响I型和II型小胶质细胞的形态和数量。环境富集和感染相互作用可能会导致小胶质细胞形态变化，以至于无法从富集环境中区分出感染小鼠的I型和II型形态表型。在形态复杂性与TNFα外周血之间发现显着的线性相关性。我们的研究结果表明，久坐的和活跃的小鼠模型表现出不同的小胶质细胞反应和对DENV1病毒的全身性非神经营养性感染的外周炎症。