Rose David M, Alon Ronen, Ginsberg Mark H
Department of Medicine, University of California, and VA Healthcare System, San Diego, CA, USA.
Immunol Rev. 2007 Aug;218:126-34. doi: 10.1111/j.1600-065X.2007.00536.x.
The movement of leukocytes from the blood into peripheral tissues plays a key role in immunity as well as chronic inflammatory and autoimmune diseases. The shear force of blood flow presents special challenges to leukocytes as they establish adhesion on the vascular endothelium and migrate into the underlying tissues. Integrins are a family of cell adhesion and signaling molecules, whose function can be regulated to meet these challenges. The affinity of integrins for their vascular ligands can be stimulated in subseconds by chemoattractant signaling. This aids in inducing leukocyte adhesion under flow conditions. Further, linkage of these integrins to the actin cytoskeleton also helps to establish adhesion to the endothelium under flow conditions. In the case of alpha4beta1 integrins, this linkage of the integrin to the cytoskeleton is mediated in part by the binding of paxillin to the alpha4 integrin subunit and the subsequent binding of paxillin to the cytoskeleton molecule talin. The movement of leukocytes along the vascular endothelium and in between endothelial cells requires the temporal and spatial regulation of small guanosine triphosphatases, such as Rac1. We describe mechanisms through which alpha4beta1 integrin signaling regulates appropriate Rac activation to drive leukocyte migration.
白细胞从血液进入外周组织的过程在免疫以及慢性炎症和自身免疫性疾病中起着关键作用。当白细胞在血管内皮上建立黏附并迁移到下层组织时，血流的剪切力给它们带来了特殊挑战。整合素是一类细胞黏附和信号分子家族，其功能可被调节以应对这些挑战。趋化因子信号可在数秒内刺激整合素与血管配体的亲和力，这有助于在流动条件下诱导白细胞黏附。此外，这些整合素与肌动蛋白细胞骨架的连接也有助于在流动条件下与内皮建立黏附。就α4β1整合素而言，整合素与细胞骨架的这种连接部分是由桩蛋白与α4整合素亚基的结合以及随后桩蛋白与细胞骨架分子踝蛋白的结合介导的。白细胞沿血管内皮以及在内皮细胞之间的移动需要小GTP酶（如Rac1）的时空调节。我们描述了α4β1整合素信号调节适当的Rac激活以驱动白细胞迁移的机制。
