Brain Interleukin-17A contributes to neuroinflammation and cardiac dysfunction in rats with myocardial infarction.
Brain Interleukin-17A contributes to neuroinflammation and cardiac dysfunction in rats with myocardial infarction.
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脑白细胞介素-17 A参与心肌梗死大鼠的神经炎症和心功能障碍
DOI：
10.3389/fnins.2022.1032434
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发表时间：
2022
影响因子：
4.3
通讯作者：
Wei, Shun-Guang
中科院分区：
文献类型：
--
作者：
Yu, Yang;Weiss, Robert M. M.;Wei, Shun-Guang
关键词：
中枢神经系统外产生的促炎细胞因子可在大脑中作用，促进交感神经激活，从而促进心力衰竭(HF)的进展。白介素17A(IL-17A)是一种关键的炎症调节因子，它协调免疫反应以促进慢性炎症，参与了HF的病理生理过程。我们以前曾报道，IL-17A作用于脑内，特别是在下丘脑室旁核(PVN)，增加炎症介质的表达，从而导致交感神经流出。本研究试图确定在心肌梗死诱导的心衰大鼠模型中，IL-17A水平是否升高，如果是，脑内IL-17A表达增加是否导致这种疾病背景下的神经炎症和心功能障碍。雄性SD大鼠冠状动脉结扎(CL)诱导心力衰竭或假手术(Sham)。与假手术组相比，心力衰竭大鼠血浆IL-17A水平显著升高，于术后1周开始升高，至术后4周达到高峰。心衰大鼠脑脊液中IL-17A水平升高，且与血浆中IL-17A水平呈正相关。与假手术组相比，心力衰竭大鼠室旁核IL-17A及其受体IL-17RA的mRNA表达显著上调，而IL-17RC的表达无明显变化。通过双侧PVN微量注射IL-17RA siRNA AAV病毒基因敲除IL-17RA，可减弱促炎细胞因子和趋化因子的mRNA表达，改善交感神经激活和心功能。这些数据表明，IL-17A在HF患者脑内的高表达导致了HF患者过度的中枢性炎症状态和心功能不全。抑制脑内IL-17A/IL-17RA轴的干预措施有可能用于治疗心衰。
Proinflammatory cytokines produced outside the central nervous system can act in the brain to promote sympathetic activation that contributes to the progression of heart failure (HF). Interleukin (IL)-17A, a key inflammatory regulator which orchestrates immune responses to promote chronic inflammation, has been implicated in the pathophysiology of HF. We previously reported that IL-17A acts within the brain, particularly in the hypothalamic paraventricular nucleus (PVN), to increase expression of inflammatory mediators and, consequently, sympathetic outflow. The present study sought to determine whether IL-17A levels are elevated in a rat model of HF induced by myocardial infarction and, if so, whether increased expression of IL-17A in the brain itself contributes to neuroinflammation and cardiac dysfunction in this disease setting. Male SD rats underwent coronary artery ligation (CL) to induce HF or sham operation (SHAM). Compared with SHAM rats, HF rats exhibited significantly increased IL-17A levels in plasma, beginning within 1 week with a peak increase at 4 weeks after CL. IL-17A levels in cerebrospinal fluid (CSF) were also increased in HF rats and correlated with IL-17A levels in the plasma. The mRNA expression of IL-17A and its receptor IL-17RA, but not IL-17RC, was markedly upregulated in the PVN of HF when compared with SHAM rats. Genetic knockdown of IL-17RA by bilateral PVN microinjections of an IL-17RA siRNA AAV virus attenuated mRNA expression of proinflammatory cytokines and chemokines, and ameliorated sympathetic activation and cardiac function in HF rats. These data indicate that elevated expression of IL-17A in the brain in HF contributes to the excessive central inflammatory state and cardiac dysfunction in HF. Interventions to suppress IL-17A/IL-17RA axis in the brain have the potential for treating HF.
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影响因子：
158.5
作者：
Baeten, Dominique;Sieper, Joachim;Richards, Hanno B.
通讯作者：
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影响因子：
4.7
作者：
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Kuhlmann, Christoph R. W.
影响因子：
3
作者：
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通讯作者：
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