Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response
Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response
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DOI：
10.1161/atvbaha.109.202044
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发表时间：
2010-03-01
影响因子：
8.7
通讯作者：
Simmet, Thomas
中科院分区：
文献类型：
--
作者：
Li, Xuehua;Syrovets, Tatiana;Simmet, Thomas
树突状细胞（DC）在动脉粥样硬化的动脉中积聚，在那里它们可以调节动脉粥样硬化的发生。我们调查纤溶酶是否可能改变人DC的功能。方法和结果刺激单核细胞来源的DC与纤溶酶引起的时间依赖性肌动蛋白聚合和趋化性相媲美的标准化学引诱剂甲酰-甲硫氨酰-亮氨酰-苯丙氨酸引发的。纤溶酶触发Akt和丝裂原活化蛋白激酶的快速活化，随后是调节性肌球蛋白轻链的磷酸化和趋化性。对于趋化性DC迁移，Akt和p38以及细胞外信号调节激酶1/2丝裂原活化蛋白激酶的激活是不可或缺的，如药理学抑制剂所示。DC表达Akt 1和Akt 2，但不表达Akt 3。然而，在DC中，纤溶酶仅通过p38丝裂原活化蛋白激酶依赖性途径激活Akt 2。因此，用短发夹RNA敲低Akt 2，而不是Akt 1，阻断纤溶酶诱导的细胞外信号调节激酶1/2激活和趋化反应。此外，纤溶酶刺激的DC诱导CD 4（+）T细胞向产生干扰素-γ的促炎性Th 1表型极化。与DC和适应性免疫反应在动脉粥样硬化形成中的作用一致，我们证明了DC在人类动脉粥样硬化血管中，并表明纤溶酶在人类动脉粥样硬化病变中是丰富的，在那里它与DC共定位。结论-纤溶酶在动脉粥样硬化血管壁中的产生可能有助于DC的积累，激活适应性免疫反应，并加重动脉粥样硬化。（Arterioscler Thromb Vasc Biol.2010;30：582-590.）
Objective-Dendritic cells (DC) accumulate in atherosclerotic arteries where they can modulate atherogenesis. We investigated whether plasmin might alter the function of human DC.Methods and Results-Stimulation of monocyte-derived DC with plasmin elicited a time-dependent actin polymerization and chemotaxis comparable to that triggered by the standard chemoattractant formyl-methionyl-leucyl-phenylalanine. Plasmin triggered rapid activation of Akt and mitogen-activated protein kinases, followed by phosphorylation of the regulatory myosin light chain and chemotaxis. For the chemotactic DC migration, the activation of Akt and p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases were indispensable, as shown by pharmacological inhibitors. DC express Akt1 and Akt2, but not Akt3. However, in DC, plasmin activates exclusively Akt2 via a p38 mitogen-activated protein kinase-dependent pathway. Accordingly, knockdown of Akt2 with short-hairpin RNA, but not of Akt1, blocked the plasmin-induced extracellular signal-regulated kinase 1/2 activation and the chemotactic response. Moreover, plasmin-stimulated DC induced polarization of CD4(+) T cells toward the interferon-gamma-producing, proinflammatory Th1 phenotype. Consistent with a role for DC and adaptive immune response in atherogenesis, we demonstrate DC in human atherosclerotic vessels and show that plasmin is abundant in human atherosclerotic lesions, where it colocalizes with DC.Conclusion-Plasmin generation in the atherosclerotic vessel wall might contribute to accumulation of DC, activation of the adaptive immune response, and aggravation of atherosclerosis. (Arterioscler Thromb Vasc Biol. 2010;30:582-590.)