Transforming Growth Factor-β Signaling in T Cells Promotes Stabilization of Atherosclerotic Plaques Through an Interleukin-17-Dependent Pathway
Transforming Growth Factor-β Signaling in T Cells Promotes Stabilization of Atherosclerotic Plaques Through an Interleukin-17-Dependent Pathway
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DOI：
10.1126/scitranslmed.3006133
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发表时间：
2013-07-31
影响因子：
17.1
通讯作者：
Hansson, Goeran K.
中科院分区：
文献类型：
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作者：
Gistera, Anton;Robertson, Anna-Karin L.;Hansson, Goeran K.
适应性免疫对动脉粥样硬化有重要影响，不同T细胞亚群发挥促动脉粥样硬化和抗动脉粥样硬化作用。转化生长因子-β（TGF-β）可能促进抗动脉粥样硬化调节性T细胞或T辅助细胞17（T（H）17）细胞的发育，这取决于局部环境中的因素。我们已经讨论了T细胞中增强的TGF-β信号传导对动脉粥样硬化的影响。将T细胞特异性缺失Smad 7（一种TGF-β信号传导的有效抑制剂）的小鼠骨髓移植到高胆固醇血症Ldlr（-/-）小鼠中。Smad 7缺陷小鼠具有显著更大的动脉粥样硬化病变，其中含有大的富含胶原蛋白的帽，与更稳定的表型一致。炎性细胞因子白细胞介素-6（IL-6）在动脉粥样硬化主动脉中表达，IL-17 A和T（H）17特异性转录因子ROR γ t的mRNA在引流淋巴结中检测到增加。用中和IL-17 A抗体处理Smad 7缺陷嵌合体逆转了稳定的帽形成。IL-17 A刺激人血管平滑肌细胞产生胶原蛋白，RORgt mRNA与人动脉粥样硬化斑块生物库中的I型胶原蛋白和α-平滑肌肌动蛋白mRNA呈正相关。这些数据将IL-17 A与诱导稳定斑块表型联系起来，可能导致新的斑块稳定疗法，并应促进对接受IL-17受体阻断剂治疗的患者的心血管事件进行评估。
Adaptive immunity has a major impact on atherosclerosis, with pro- and anti-atherosclerotic effects exerted by different subpopulations of T cells. Transforming growth factor-beta (TGF-beta) may promote development either of anti-atherosclerotic regulatory T cells or of T helper 17 (T(H)17) cells, depending on factors in the local milieu. We have addressed the effect on atherosclerosis of enhanced TGF-beta signaling in T cells. Bone marrow from mice with a T cell-specific deletion of Smad7, a potent inhibitor of TGF-beta signaling, was transplanted into hypercholesterolemic Ldlr(-/-) mice. Smad7-deficient mice had significantly larger atherosclerotic lesions that contained large collagen-rich caps, consistent with a more stable phenotype. The inflammatory cytokine interleukin-6 (IL-6) was expressed in the atherosclerotic aorta, and increased mRNA for IL-17A and the T(H)17-specific transcription factor ROR gamma t were detected in draining lymph nodes. Treating Smad7-deficient chimeras with neutralizing IL-17A antibodies reversed stable cap formation. IL-17A stimulated collagen production by human vascular smooth muscle cells, and RORgt mRNA correlated positively with collagen type I and alpha-smooth muscle actin mRNA in a biobank of human atherosclerotic plaques. These data link IL-17A to induction of a stable plaque phenotype, could lead to new plaque-stabilizing therapies, and should prompt an evaluation of cardiovascular events in patients treated with IL-17 receptor blockade.