Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany; Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany;
Max-Planck-Institute of Biochemistry, Department of Molecular Medicine, Martinsried, Germany;
Blood. 2015 Dec 10;126(24):2592-600. doi: 10.1182/blood-2015-04-639310. Epub 2015 Oct 5.
Hematopoietic cells depend on integrin-mediated adhesion and signaling, which is induced by kindlin-3 and talin-1. To determine whether platelet and polymorphonuclear neutrophil (PMN) functions require specific thresholds of kindlin-3, we generated mouse strains expressing 50%, 10%, or 5% of normal kindlin-3 levels. We report that in contrast to kindlin-3-null mice, which die perinatally of severe bleeding and leukocyte adhesion deficiency, mice expressing as little as 5% of kindlin-3 were viable and protected from spontaneous bleeding and infections. However, platelet adhesion and aggregation were reduced in vitro and bleeding times extended. Similarly, leukocyte adhesion, extravasation, and bacterial clearance were diminished. Quantification of protein copy numbers revealed stoichiometric quantities of kindlin-3 and talin-1 in platelets and neutrophils, indicating that reduction of kindlin-3 in our mouse strains progressively impairs the cooperation with talin-1. Our findings show that very low levels of kindlin-3 enable basal platelet and neutrophil functions, whereas in stress situations such as injury and infection, platelets and neutrophils require a maximum of functional integrins that is achieved with high and stoichiometric quantities of kindlin-3 and talin-1.
造血细胞依赖整合素介导的黏附和信号转导，这一过程由 kindlin-3 和 talin-1 诱导。为了确定血小板和多形核中性粒细胞（PMN）的功能是否需要特定阈值的 kindlin-3，我们生成了表达正常 kindlin-3 水平的 50%、10%或 5%的小鼠品系。我们报告说，与 kindlin-3 缺失的小鼠不同，后者在围产期死于严重出血和白细胞黏附缺陷，表达低至 5%的 kindlin-3 的小鼠仍然具有活力并能防止自发性出血和感染。然而，血小板黏附和聚集在体外减少，出血时间延长。同样，白细胞黏附、渗出和细菌清除也减少。蛋白拷贝数的定量分析显示血小板和中性粒细胞中 kindlin-3 和 talin-1 的数量相当，表明我们小鼠品系中 kindlin-3 的减少逐渐损害了与 talin-1 的协同作用。我们的研究结果表明，极低水平的 kindlin-3 能够维持基础的血小板和中性粒细胞功能，而在创伤和感染等应激情况下，血小板和中性粒细胞需要最大数量的功能性整合素来实现，这需要高浓度和相当数量的 kindlin-3 和 talin-1。
