The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils
The GTPase-activating protein ARAP3 regulates chemotaxis and adhesion-dependent processes in neutrophils
复制标题
DOI：
10.1182/blood-2010-10-312959
复制
发表时间：
2011-07-28
期刊：
影响因子：
20.3
通讯作者：
Vermeren, Sonja
中科院分区：
文献类型：
--
作者：
Gambardella, Laure;Anderson, Karen E.;Vermeren, Sonja
中性粒细胞形成先天免疫应答的重要部分，但同时它们的不适当激活有助于自身免疫性疾病。许多分子组分参与微调中性粒细胞功能。我们在这里报告的第一个表征的作用ARAP 3，PI 3 K和RAP调节GTP酶激活蛋白RhoA和Arf 6在小鼠中性粒细胞。我们发现，缺乏ARAP 3的中性粒细胞在体外和体内被预激活，表现出增加的β 2整合素亲和力和亲合力。ARAP 3缺陷型中性粒细胞在体外的几种粘附依赖性情况下反应过度，包括活性氧簇的形成、粘附、扩散和颗粒释放。ARAP 3缺陷细胞在体外流动条件下和体内血管壁上粘附更牢固。最后，ARAP 3的缺失干扰了整联蛋白依赖的中性粒细胞趋化性。本研究的结果表明Rap下游的ARAP 3的重要功能。通过调节β 2整合素活性，ARAP 3保护中性粒细胞处于静止状态，除非被激活。（血。2011; 118（4）：1087-1098）
Neutrophils form a vital part of the innate immune response, but at the same time their inappropriate activation contributes to autoimmune diseases. Many molecular components are involved in fine-tuning neutrophil function. We report here the first characterization of the role of ARAP3, a PI3K and Rap-regulated GTPase-activating protein for RhoA and Arf6 in murine neutrophils. We show that neutrophils lacking ARAP3 are preactivated in vitro and in vivo, exhibiting increased beta 2 integrin affinity and avidity. ARAP3-deficient neutrophils are hyperresponsive in several adhesion-dependent situations in vitro, including the formation of reactive oxygen species, adhesion, spreading, and granule release. ARAP3-deficient cells adhere more firmly under flow conditions in vitro and to the vessel wall in vivo. Finally, loss of ARAP3 interferes with integrin-dependent neutrophil chemotaxis. The results of the present study suggest an important function of ARAP3 downstream of Rap. By modulating beta 2 integrin activity, ARAP3 guards neutrophils in their quiescent state unless activated. (Blood. 2011; 118(4):1087-1098)