Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension
Elevated bone marrow sympathetic drive precedes systemic inflammation in angiotensin II hypertension
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DOI：
10.1152/ajpheart.00510.2018
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发表时间：
2019-08-01
影响因子：
4.8
通讯作者：
Zubcevic, Jasenka
中科院分区：
文献类型：
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作者：
Ahmari, Niousha;Santisteban, Monica M.;Zubcevic, Jasenka
交感神经系统活性增加是高血压（HTN）的标志，并且在其病理生理学中与免疫系统反应改变有关。然而，HTN中神经免疫相互作用的确切机制仍然难以捉摸。我们先前已经在HTN的啮齿动物模型中显示了升高的对骨髓（BM）的交感神经驱动与激活的BM免疫细胞之间的关联。此外，在HTN的啮齿动物模型中也观察到小胶质细胞依赖性神经炎症。然而，中枢和全身炎症反应与交感神经驱动之间的因果关系仍然未知。这些观察结果使我们假设股BM交感神经活动（fSNA）的增加引发了导致血压（BP）升高的级联事件。在这里，我们研究了BM交感神经驱动，中枢和外周免疫系统的激活，以及导致建立HTN的事件中BP增加之间的时间关系。本研究表明，血管紧张素II（ANG II）的中央输液诱导早期小胶质细胞激活下丘脑室旁核，这之前增加的fSNA。反过来，fSNA的激活与CD4（+）产生和释放增加的时间相关。IL 17（+）T细胞和其他促炎细胞进入循环和血压升高，而CD4（+）细胞浸润到室旁核标志着ANG II HTN的建立。这项研究确定了参与神经免疫相互作用的细胞和分子机制，在早期和建立阶段的啮齿动物血管紧张素II HTN。新&值得注意的是，早期小胶质细胞激活室旁核先于交感神经激活骨髓。这导致骨髓免疫细胞增加，并将其释放到循环中，并导致血压升高。CD 4（+）T细胞浸润到室旁核室旁核标志着晚期高血压。
Increased sympathetic nervous system activity is a hallmark of hypertension (HTN), and it is implicated in altered immune system responses in its pathophysiology. However, the precise mechanisms of neural-immune interaction in HTN remain elusive. We have previously shown an association between elevated sympathetic drive to the bone marrow (BM) and activated BM immune cells in rodent models of HTN. Moreover, microglial-dependent neuroinflammation is also seen in rodent models of HTN. However, the cause-effect relationship between central and systemic inflammatory responses and the sympathetic drive remains unknown. These observations led us to hypothesize that increase in the femoral BM sympathetic nerve activity (fSNA) initiates a cascade of events leading to increase in blood pressure (BP). Here, we investigated the temporal relationship between the BM sympathetic drive, activation of the central and peripheral immune system, and increase in BP in the events leading to established HTN. The present study demonstrates that central infusion of angiotensin II (ANG II) induces early microglial activation in the paraventricular nucleus of hypothalamus, which preceded increase in the fSNA. In turn, activation of fSNA correlated with the timing of increased production and release of CD4(+). IL17(+) T cells and other proinflammatory cells into circulation and elevation in BP, whereas infiltration of CD4(+) cells to the paraventricular nucleus marked establishment of ANG II HTN. This study identifies cellular and molecular mechanisms involved in neural-immune interactions in early and established stages of rodent ANG II HTN.NEW & NOTEWORTHY Early microglia activation in paraventricular nucleus precedes sympathetic activation of the bone marrow. This leads to increased bone marrow immune cells and their release into circulation and an increase in blood pressure. Infiltration of CD4(+) T cells into paraventricular nucleus paraventricular nucleus marks late hypertension.