Quast Thomas, Tappertzhofen Barbara, Schild Cora, Grell Jessica, Czeloth Niklas, Förster Reinhold, Alon Ronen, Fraemohs Line, Dreck Katrin, Weber Christian, Lämmermann Tim, Sixt Michael, Kolanus Waldemar
Life and Medical Sciences Institute, Laboratory for Molecular Immunology, University of Bonn, Bonn, Germany.
Blood. 2009 Jun 4;113(23):5801-10. doi: 10.1182/blood-2008-08-176123. Epub 2009 Apr 3.
Adhesion and motility of mammalian leukocytes are essential requirements for innate and adaptive immune defense mechanisms. We show here that the guanine nucleotide exchange factor cytohesin-1, which had previously been demonstrated to be an important component of beta-2 integrin activation in lymphocytes, regulates the activation of the small GTPase RhoA in primary dendritic cells (DCs). Cytohesin-1 and RhoA are both required for the induction of chemokine-dependent conformational changes of the integrin beta-2 subunit of DCs during adhesion under physiological flow conditions. Furthermore, use of RNAi in murine bone marrow DCs (BM-DCs) revealed that interference with cytohesin-1 signaling impairs migration of wild-type dendritic cells in complex 3D environments and in vivo. This phenotype was not observed in the complete absence of integrins. We thus demonstrate an essential role of cytohesin-1/RhoA during ameboid migration in the presence of integrins and further suggest that DCs without integrins switch to a different migration mode.
哺乳动物白细胞的黏附与运动能力是先天性和适应性免疫防御机制的基本要求。我们在此表明，鸟嘌呤核苷酸交换因子细胞衔接蛋白-1（此前已被证明是淋巴细胞中β2整合素激活的重要组成部分）可调节原代树突状细胞（DCs）中小GTP酶RhoA的激活。在生理流动条件下黏附过程中，细胞衔接蛋白-1和RhoA都是DCs整合素β2亚基趋化因子依赖性构象变化诱导所必需的。此外，在小鼠骨髓DCs（BM-DCs）中使用RNA干扰技术显示，干扰细胞衔接蛋白-1信号会损害野生型树突状细胞在复杂三维环境中和体内的迁移。在完全没有整合素的情况下未观察到这种表型。因此，我们证明了在整合素存在的情况下，细胞衔接蛋白-1/RhoA在阿米巴样迁移过程中的重要作用，并进一步表明没有整合素的DCs会切换到不同的迁移模式。
