Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK; and.
Blood Adv. 2018 Apr 10;2(7):731-744. doi: 10.1182/bloodadvances.2017015602.
Rolling neutrophils receive signals while engaging P- and E-selectin and chemokines on inflamed endothelium. Selectin signaling activates β2 integrins to slow rolling velocities. Chemokine signaling activates β2 integrins to cause arrest. Despite extensive study, key aspects of these signaling cascades remain unresolved. Using complementary in vitro and in vivo assays, we found that selectin and chemokine signals in neutrophils triggered Rap1a-dependent and phosphatidylinositol-4-phosphate 5-kinase γ (PIP5Kγ90)-dependent pathways that induce integrin-dependent slow rolling and arrest. Interruption of both pathways, but not either pathway alone, blocked talin-1 recruitment to and activation of integrins. An isoform of PIP5Kγ90 lacking the talin-binding domain (PIP5Kγ87) could not activate integrins. Chemokines, but not selectins, used phosphatidylinositol-4,5-bisphosphate 3-kinase γ (PI3Kγ) in cooperation with Rap1a to mediate integrin-dependent slow rolling (at low chemokine concentrations), as well as arrest (at high chemokine concentrations). High levels of chemokines activated β2 integrins without selectin signals. When chemokines were limiting, they synergized with selectins to activate β2 integrins.
滚动中的中性粒细胞在与炎症内皮细胞上的 P 选择素和 E 选择素及趋化因子结合时会接收到信号。选择素信号激活β2 整合素以降低滚动速度。趋化因子信号激活β2 整合素以导致其黏附。尽管进行了广泛的研究，但这些信号级联的关键方面仍未得到解决。通过互补的体外和体内测定，我们发现中性粒细胞中的选择素和趋化因子信号触发了 Rap1a 依赖性和磷脂酰肌醇-4-磷酸 5-激酶γ（PIP5Kγ90）依赖性途径，这些途径诱导整合素依赖性缓慢滚动和黏附。阻断这两种途径，但不是单独阻断任何一种途径，都可以阻止 talin-1 募集到整合素并激活整合素。缺乏 talin 结合结构域的 PIP5Kγ90 同工型（PIP5Kγ87）不能激活整合素。趋化因子而非选择素，与 Rap1a 合作使用磷脂酰肌醇-4,5-二磷酸 3-激酶γ（PI3Kγ）来介导整合素依赖性的缓慢滚动（在低浓度趋化因子的情况下）以及黏附（在高浓度趋化因子的情况下）。高浓度的趋化因子在没有选择素信号的情况下激活β2 整合素。当趋化因子有限时，它们与选择素协同作用以激活β2 整合素。
