Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke
Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke
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DOI：
10.1126/scitranslmed.aao1313
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发表时间：
2018-03-14
影响因子：
17.1
通讯作者：
Liesz, Arthur
中科院分区：
文献类型：
--
作者：
Roth, Stefan;Singh, Vikramjeet;Liesz, Arthur
中风引起多相的全身免疫反应，但这种反应对动脉粥样硬化的后果--血管事件复发的主要来源--还没有被彻底研究。我们发现，中风通过警报蛋白介导的血管炎症传播加剧动脉粥样硬化进展。原型脑释放的alarmin高迁移率族蛋白1蛋白通过晚期糖基化终产物受体（receptor for advanced glycation end products，ERK）信号级联反应诱导单核细胞和内皮细胞活化，并增加斑块负荷和脆弱性。通过CC-趋化因子配体2-CC-趋化因子受体2型途径募集活化的单核细胞在卒中诱导的血管炎症中至关重要。中和循环中的alarmin或敲低alarmin可减弱动脉粥样硬化的进展。堵塞。3-肾上腺素受体减弱了中风后骨髓单核细胞的流出，而循环中的alarmins的中和需要减少系统性单核细胞活化和主动脉侵袭。我们的研究结果确定了交感神经应激反应和警报素驱动的炎症的协同作用，作为中风后动脉粥样硬化进展加剧的关键机制。
Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-a major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of. 3-adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke.