Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice.
Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice.
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转录-3信号传导的白介素-6信号换能器和活化剂通过T-B-helper淋巴细胞17-Interleukin 17 Interleukin 17 Axis介导了由血管紧张素II诱导的主动脉夹层。
DOI：
10.1161/atvbaha.112.301049
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Brasier AR
中科院分区：
文献类型：
--
作者：
Ju X;Ijaz T;Sun H;Ray S;Lejeune W;Lee C;Recinos A 3rd;Guo DC;Milewicz DM;Tilton RG;Brasier AR
血管紧张素II （Ang II）信号失调诱导局部血管白介素-6 （IL-6）分泌，产生白细胞浸润和危及生命的主动脉夹层。IL-6信号诱导白细胞募集的确切机制尚不清楚。辅助性t - 17淋巴细胞（Th17）与血管病理有关，但其在主动脉夹层发生中的作用尚不清楚。在C57BL/6小鼠中，我们检测了IL-6-STAT3信号与th17诱导的炎症在Ang ii诱导的夹层形成中的关系。angii输注诱导C57BL/6小鼠主动脉夹层和CD4+-白细胞介素17A （IL-17A）表达、Th17细胞积累。在IL-6−/−小鼠中，局部Th17激活减弱，巨噬细胞募集，主动脉夹层发生率降低。为了确定Th17淋巴细胞的病理作用，我们用IL-17A中和抗体（IL17A NAb）治疗注入Ang II的小鼠，或在基因缺陷的小鼠中注入Ang II，发现主动脉趋化因子MCP-1产生和巨噬细胞募集减少，导致主动脉夹层减少。在IL17ANAb实验中，这种作用与血压无关。应用细胞渗透性STAT3抑制剂下调IL-6通路，降低主动脉扩张和Th17细胞募集。我们还观察到胸主动脉夹层患者的主动脉Th17浸润和IL-17 mRNA表达增加。最后，我们发现Ang II介导的主动脉夹层的发生与血压变化无关。我们的研究结果表明，IL-6-STAT3信号通路聚集在巨噬细胞募集上游的Th17募集和IL-17A信号通路，介导主动脉夹层。
Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life-threatening aortic dissections. Precise mechanism(s) by which IL-6 signaling induces leukocyte recruitment remain(s) unknown. T-helper 17lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6-STAT3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. Ang II infusion induced aortic dissections and CD4+-interleukin 17A (IL-17A)-expressing, Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6−/− mice. To determine pathological roles of Th17 lymphocytes, we treated Ang II infused mice with IL-17A neutralizing antibody (IL17A NAb), or infused Ang II in genetically deficientIL-17A mice, and found decreased aortic chemokine MCP-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL17ANAb experiment. Application of a cell-permeable STAT3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Lastly, we found that Ang II mediated aortic dissections occurred independent of blood pressure changes. Our results indicate that the IL-6-STAT3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections.