Silva Talita M, Chaar Laiali J, Silva Reinaldo C, Takakura Ana C, Câmara Niels O, Antunes Vagner R, Moreira Thiago S
Department of Physiology and Biophysics, University of São Paulo, 05508-000, São Paulo, SP, Brazil.
Department of Immunology, University of São Paulo, 05508-000, São Paulo, SP, Brazil.
Exp Physiol. 2018 Jun;103(6):884-895. doi: 10.1113/EP086780. Epub 2018 Apr 16.
What is the central question of this study? Microglia are presumed to be the source of inflammatory mediators that contribute to hypoxia-induced neuroinflammation. However, the relationship between microglial activity during hypoxia and inflammatory responses in specific autonomic brain regions is not well understood. Therefore, we hypothesized that acute hypoxia initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. What is the main finding and its importance? Acute hypoxia initiated neuroinflammatory mechanisms specifically in brain autonomic nuclei responsible for cardiorespiratory control, i.e. the rostral ventrolateral medulla and paraventricular nucleus of the hypothalamus. Our findings emphasize the importance of microglia for the maintenance of autonomic adjustments during physiological challenges, such as hypoxia, or during cardiorespiratory reflex activation elicited by the arterial chemoreceptors.
Prolonged and continuous exposure of mammals to a low oxygen environment (chronic hypoxia) elicits remarkable morphological and physiological adjustments. These include altered gene expression, increased peripheral chemosensitivity, enhanced respiratory drive and sympathoexcitation. The current study examines the hypothesis that acute hypoxia (AH) initiates an immune response in the central nervous system elicited by an increased expression of inflammatory mediators in specific brain areas related to autonomic control. Male Wistar rats pretreated with vehicle or minocycline (30 mg kg day for 5 days) were subjected to AH (8% O , balance N ) or normoxia (21% O ) for 3 h. AH increased interleukin (IL)-6, IL-1β and matrix metalloprotease 9 (MMP9) mRNA expression in the paraventricular nucleus of the hypothalamus (PVH) and rostral ventrolateral medulla (RVLM) and tumour necrosis factor α (TNFα) in the RVLM. Treatment with minocycline, an inhibitor of microglial activation, decreased IL-1β, TNFα and MMP9 mRNA expression in the RVLM, and increased IL-6 mRNA expression in the RVLM and PVH of rats exposed to AH. Minocycline treatment also elicited a decrease in the number of activated neurons in the RVLM/C1 neurons (expressed as Fos /tyrosine hydroxylase ), the number of Fos-activated neurons in the PVH and the increase in ventilation elicited by AH. When viewed together, these results suggest that AH modulates the expression of inflammatory mediators in autonomic brain nuclei that may be involved in the responses to chemoreceptor activation.
本研究的核心问题是什么？小胶质细胞被认为是导致缺氧诱导神经炎症的炎症介质来源。然而，缺氧期间小胶质细胞活性与特定自主神经脑区炎症反应之间的关系尚不清楚。因此，我们假设急性缺氧会引发中枢神经系统的免疫反应，这种反应是由与自主控制相关的特定脑区中炎症介质表达增加所引起的。主要发现及其重要性是什么？急性缺氧特别在负责心肺控制的脑自主神经核团，即延髓头端腹外侧区和下丘脑室旁核中引发神经炎症机制。我们的发现强调了小胶质细胞在诸如缺氧等生理挑战期间或在动脉化学感受器引发的心肺反射激活期间维持自主调节的重要性。
哺乳动物长期持续暴露于低氧环境（慢性缺氧）会引发显著的形态和生理调节。这些调节包括基因表达改变、外周化学敏感性增加、呼吸驱动增强和交感神经兴奋。本研究检验了急性缺氧（AH）会引发中枢神经系统免疫反应这一假设，该反应由与自主控制相关的特定脑区中炎症介质表达增加所引起。用溶剂或米诺环素（30毫克/千克/天，持续5天）预处理过的雄性Wistar大鼠接受3小时的AH（8%氧气，其余为氮气）或常氧（21%氧气）处理。AH增加了下丘脑室旁核（PVH）和延髓头端腹外侧区（RVLM）中白细胞介素（IL）-6、IL-1β和基质金属蛋白酶9（MMP9）的mRNA表达，以及RVLM中肿瘤坏死因子α（TNFα）的表达。用小胶质细胞激活抑制剂米诺环素处理，可降低RVLM中IL-1β、TNFα和MMP9的mRNA表达，并增加暴露于AH的大鼠RVLM和PVH中IL-6的mRNA表达。米诺环素处理还使RVLM/C1神经元（以Fos /酪氨酸羟化酶表示）中活化神经元的数量、PVH中Fos活化神经元的数量以及AH引起通气增加有所减少。综合来看，这些结果表明AH调节自主神经脑核中炎症介质的表达，这些介质可能参与对化学感受器激活的反应。
