Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling
Integrin activation by P-Rex1 is required for selectin-mediated slow leukocyte rolling and intravascular crawling
复制标题
DOI：
10.1182/blood-2012-09-457085
复制
发表时间：
2013-03-21
期刊：
影响因子：
20.3
通讯作者：
Zarbock, Alexander
中科院分区：
文献类型：
--
作者：
Herter, Jan M.;Rossaint, Jan;Zarbock, Alexander
整合素的激活对白细胞的功能至关重要。白细胞上整合素活化受损是人类白细胞黏附缺陷综合征的特征，其特征是白细胞募集受损和反复感染。在炎症中，白细胞在与微血管系统接触时收集不同的信号，激活信号通路，导致整合素激活和白细胞募集。我们报道了P-REx1，一种RAC特异性的鸟嘌呤核苷酸交换因子，在整合素激活和白细胞募集中的作用。我们发现，P-REx1是诱导选择素介导的淋巴细胞功能相关抗原-1(LFA-1)延伸所必需的，该延伸对应于中等亲和力并诱导缓慢的白细胞滚动，而P-REx1不参与诱导高亲和力构象的LFA-1，而LFA-1是白细胞停止所必需的。此外，我们还证明P-REx1参与了Mac-1依赖的血管内爬行。在体内，依赖LFA-1的慢滚和依赖Mac-1的爬行在P-Rex1(-/-)白细胞中都存在缺陷，而在P-Rex1缺乏的白细胞中，趋化因子诱导的停滞和黏附后强化保持不变。Rac1参与E-选择素介导的缓慢滚动和爬行。在体内，在缺血-再灌注诱导的急性肾损伤模型中，取消选择素介导的整合素激活有助于减少P-REx1缺陷小鼠的中性粒细胞募集和肾脏损伤。我们认为P-REx1在LFA-1和Mac-1的激活中起着不同的作用。
Integrin activation is essential for the function of leukocytes. Impaired integrin activation on leukocytes is the hallmark of the leukocyte adhesion deficiency syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. In inflammation, leukocytes collect different signals during the contact with the microvasculature, which activate signaling pathways leading to integrin activation and leukocyte recruitment. We report the role of P-Rex1, a Rac-specific guanine nucleotide exchanging factor, in integrin activation and leukocyte recruitment. We find that P-Rex1 is required for inducing selectin-mediated lymphocyte function-associated antigen-1 (LFA-1) extension that corresponds to intermediate affinity and induces slow leukocyte rolling, whereas P-Rex1 is not involved in the induction of the high-affinity conformation of LFA-1 obligatory for leukocyte arrest. Furthermore, we demonstrate that P-Rex1 is involved in Mac-1-dependent intravascular crawling. In vivo, both LFA-1-dependent slow rolling and Mac-1-dependent crawling are defective in P-Rex1(-/-) leukocytes, whereas chemokine-induced arrest and postadhesion strengthening remain intact in P-Rex1-deficient leukocytes. Rac1 is involved in E-selectin-mediated slow rolling and crawling. In vivo, in an ischemia-reperfusion-induced model of acute kidney injury, abolished selectin-mediated integrin activation contributed to decreased neutrophil recruitment and reduced kidney damage in P-Rex1-deficient mice. We conclude that P-Rex1 serves distinct functions in LFA-1 and Mac-1 activation.