CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation
CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation
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DOI：
10.1182/blood-2017-03-768507
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发表时间：
2017-11-09
期刊：
影响因子：
20.3
通讯作者：
Nigrovic, Peter A.
中科院分区：
文献类型：
--
作者：
Bai, Ming;Grieshaber-Bouyer, Ricardo;Nigrovic, Peter A.
CD 177是一种糖基磷脂酰肌醇（GPI）锚定蛋白，由不同比例的人中性粒细胞表达，介导抗神经细胞胞浆抗体抗原蛋白酶3的表面表达。CD 177与β 2整联蛋白相关，并识别血小板内皮细胞粘附分子1（PECAM-1），表明在中性粒细胞迁移中的作用。然而，CD 177（阳性）中性粒细胞在体内没有表现出明显的迁移优势，尽管在体外跨内皮迁移的CD 177结扎中断。我们试图理解这个悖论。使用PECAM-1非依赖性transwell系统，我们发现CD 177（阳性）和CD 177（阴性）中性粒细胞迁移。CD 177连接选择性地损害了CD 177（阳性）中性粒细胞的迁移，这种作用是通过transwell膜上的固定和细胞扩散介导的。相应地，CD 177连接增强了其与β 2整合素的相互作用，如荧光寿命成像显微镜所示，导致整合素介导的Src和细胞外信号调节激酶（ERK）的磷酸化。CD 177驱动的细胞活化增强了表面β 2整合素的表达和亲和力，损害了整合素附着的内化，并导致ERK介导的趋化因子信号转导的减弱。我们的结论是，CD 177信号在β 2整合素依赖的方式来编排一套激活介导的机制，损害人类中性粒细胞迁移。
CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with beta 2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177(pos) neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177(pos) and CD177(neg) neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177(pos) neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with beta 2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177-driven cell activation enhanced surface beta 2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a beta 2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration.