Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
Circ Res. 2012 Oct 12;111(9):1190-7. doi: 10.1161/CIRCRESAHA.112.277475. Epub 2012 Aug 17.
Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II (Ang II) induces hypertension and is associated with proinflammatory immune responses.
Our goal was to define the innate immune response in a model of genetic hypertension and the influences of cholinergic stimulation and Ang II.
Studies were conducted on 4- to 5-week-old prehypertensive spontaneously hypertensive rats (SHRs) and age-matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were preexposed to nicotine or Ang II before Toll-like receptor (TLR) activation. Culture supernatants were tested for cytokines (tumor necrosis factor-α, interleukin [IL]-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY rats and SHRs. Nicotine and Ang II enhanced this TLR-mediated IL-6 response in prehypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR-mediated IL-6 response in WKY rats, whereas Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8-mediated IL-6 and IL-1β responses in prehypertensive SHRs but suppressed these responses in WKY rats. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the prehypertensive SHR spleen but not in WKY.
There is a pronounced anti-inflammatory nicotinic/cholinergic modulation of the innate immune system in WKY rats, which is reversed in prehypertensive SHRs. The results support the novel concept that neurohormonal regulation of the innate immune system plays a role in the pathogenesis of genetic hypertension and provide putative molecular targets for treatment of hypertension.
炎症和自主神经功能障碍是高血压病理生理学的基础。胆碱能刺激可抑制固有免疫反应。血管紧张素 II（Ang II）可引起高血压，并与促炎免疫反应有关。
我们的目标是在遗传高血压模型中确定固有免疫反应，以及胆碱能刺激和 Ang II 的影响。
研究在 4-5 周龄的前期高血压自发性高血压大鼠（SHR）和年龄匹配的正常血压 Wistar Kyoto（WKY）大鼠中进行。分离的脾细胞在 Toll 样受体（TLR）激活前预先暴露于尼古丁或 Ang II。检测细胞培养上清液中的细胞因子（肿瘤坏死因子-α、白细胞介素[IL]-10 和 IL-6）。TLR7/8 和 TLR9 激活时，TLR 介导的细胞因子反应最为明显，WKY 大鼠和 SHR 之间相似。尼古丁和 Ang II 增强了前期高血压 SHR 脾细胞中 TLR 介导的 IL-6 反应。相反，尼古丁抑制了 WKY 大鼠 TLR 介导的 IL-6 反应，而 Ang II 没有影响。在体内，尼古丁增强了前期高血压 SHR 血浆中 TLR7/8 介导的 IL-6 和 IL-1β 反应，但在 WKY 大鼠中抑制了这些反应。流式细胞术显示 CD161+固有免疫细胞群体增加，在前期高血压 SHR 脾脏中，尼古丁增强了该群体，但在 WKY 大鼠中没有。
在 WKY 大鼠中，固有免疫系统存在明显的抗炎性烟碱/胆碱能调节，而在前期高血压 SHR 中则被逆转。结果支持神经激素对固有免疫系统的调节在遗传高血压发病机制中起作用的新概念，并为高血压的治疗提供了潜在的分子靶点。
