Mutation in the CD45 Inhibitory Wedge Modulates Integrin Activation and Leukocyte Recruitment during Inflammation
Mutation in the CD45 Inhibitory Wedge Modulates Integrin Activation and Leukocyte Recruitment during Inflammation
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DOI：
10.4049/jimmunol.1401646
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发表时间：
2015-01-15
影响因子：
4.4
通讯作者：
Zarbock, Alexander
中科院分区：
文献类型：
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作者：
Germena, Giulia;Volmering, Stephanie;Zarbock, Alexander
中性粒细胞募集到炎症部位在宿主防御中起着关键作用。SRC家族激酶(SFK)的激活是整合素和趋化因子信号转导以及免疫细胞功能所必需的。受体样蛋白酪氨酸磷酸酶CD45正向调节作用于SFK活性的趋化信号。为了进一步研究CD45在中性粒细胞募集和功能中的作用，我们分析了携带单点突变(CD45E613R)的转基因小鼠，CD45E613R是结构性激活CD45的基因。通过活体显微镜实验，我们证明了CD45E613R突变小鼠白细胞募集级联的不同步骤受到影响。与野生型中性粒细胞相比，CD45E613R突变型中性粒细胞的滚动速度降低，从而导致贴壁细胞数量增加。对β(2)整合素LFA-1和巨噬细胞-1抗原(Mac-1)的分析表明，CD45E613R突变的中性粒细胞中，LFA-1的粘附性受损，亲和力增强，而Mac-1的粘附性增加。与野生型中性粒细胞相比，CD45E613R突变型中性粒细胞的Mac-1黏附性增强，中性粒细胞爬行能力减弱。在大肠杆菌肺部感染模型中，CD45E613R小鼠表现出中性粒细胞进入肺泡室的减少，这导致肺中CFU的数量增加。我们的数据表明，CD45E613R突变在炎症过程中调节整合素的激活和白细胞的募集。
Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. Src family kinases (SFKs) activation is required for integrin and chemokine signaling as well as immune cell function. The receptor-like protein tyrosine phosphatase CD45 positively regulates chemoattractant signaling acting on SFK activity. To further investigate the role of CD45 in neutrophil recruitment and function, we analyzed transgenic mice carrying a single point mutation (CD45E613R), which constitutively activates CD45. By using intravital microscopy experiments, we demonstrated that different steps of the leukocyte recruitment cascade were affected in CD45E613R mutant mice. The rolling velocity of CD45E613R mutant neutrophils was decreased compared with wild-type neutrophils that subsequently resulted in an increased number of adherent cells. The analysis of beta(2) integrins LFA-1 and macrophage-1 Ag (Mac-1) showed that in CD45E613R mutant neutrophils LFA-1 adhesiveness was impaired, and avidity was enhanced, whereas Mac-1 adhesiveness was increased. Because of the increased Mac-1 adhesiveness, neutrophil crawling was impaired in CD45E613R mutant compared with wild-type neutrophils. In an Escherichia coli lung infection model, CD45E613R mice displayed a decreased neutrophil recruitment into the alveolar compartment, which resulted in an increased number of CFUs in the lung. Our data demonstrate that the CD45E613R mutation modulates integrin activation and leukocyte recruitment during inflammation.