Inositide Laboratory, The Babraham Institute, Cambridge, UK.
Blood. 2011 Jul 28;118(4):1087-98. doi: 10.1182/blood-2010-10-312959. Epub 2011 Apr 13.
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 β2 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 β2 integrin activity, ARAP3 guards neutrophils in their quiescent state unless activated.
中性粒细胞是先天免疫反应的重要组成部分，但同时它们的异常激活也会导致自身免疫性疾病。许多分子成分参与了中性粒细胞功能的精细调节。我们在这里首次描述了 ARAP3 在调节小鼠中性粒细胞中 RhoA 和 Arf6 的 PI3K 和 Rap 调节 GTP 酶激活蛋白功能中的作用。我们发现缺乏 ARAP3 的中性粒细胞在体外和体内预先被激活，表现出增加的β2 整合素亲和力和活性。ARAP3 缺陷型中性粒细胞在几种粘附依赖性的体外情况中表现出过度反应，包括活性氧物质的形成、粘附、伸展和颗粒释放。ARAP3 缺陷型细胞在体外的流动条件下和体内的血管壁上粘附得更牢固。最后，ARAP3 的缺失干扰了整合素依赖性中性粒细胞的趋化作用。本研究的结果表明，ARAP3 在 Rap 下游具有重要的功能。通过调节β2 整合素的活性，ARAP3 在中性粒细胞未被激活时保持其静止状态。
