The Mechanisms Involved in Chemotaxis of Immune and Cancer Cells

我们有几个项目。 1.天然免疫的一种教条是，中性粒细胞利用趋化因子GPCRs通过趋化作用追逐细菌，然后利用吞噬细胞受体与酪氨酸激酶偶联，通过吞噬作用破坏调理细菌。我们目前的工作已经改变了这一教条，表明G蛋白偶联甲酰肽受体(FPR)直接介导中性粒细胞吞噬。缺乏甲酰肽受体(FPR1/2-/-)的小鼠中性粒细胞在吞噬大肠杆菌和化学诱导剂fMLP包被的小球方面存在缺陷。固定在小球表面的fMLP与FPR相互作用，触发钙反应，诱导肌动蛋白聚合，形成吞噬小球的吞噬杯。趋化因子GPCR/GI信号和吞噬细胞受体/酪氨酸激酶信号通路相互独立地促进包被趋化因子或免疫球蛋白调理素珠的吞噬作用。因此，除了吞噬受体介导的吞噬作用外，中性粒细胞还利用趋化因子GPCR/GI信号来介导吞噬作用，以对抗入侵的细菌(Wen Etal，2019)。 2.中性粒细胞通过适应机制感知并通过大范围的趋化梯度迁移。在这里，我们揭示了CPARI，一个RAS的负调控因子，控制着GPCR刺激的人中性粒细胞中的RAS信号。缺乏Capri(Caprikd)的细胞表现出显著的AKT、GSK3和cofilin的磷酸化，导致肌动蛋白过度聚合和随后的中性粒细胞趋化缺陷。Caprikd细胞仅在高浓度时出现趋化缺陷，而在低浓度梯度下不显示趋化缺陷，值得注意的是，由于其较高的敏感性，Caprikd细胞在亚响应性浓度的趋化梯度中表现出更好的趋化能力。综上所述，我们揭示了Capri控制GPCRi介导的适应，并降低中性粒细胞对趋化的敏感性。

We several projects. 1. A dogma of innate immunity is that neutrophils use chemoattractant GPCRs to chase bacteria through chemotaxis and then use phagocytic receptors coupled with tyrosine kinases to destroy opsonized bacteria via phagocytosis. Our current work has changed this dogma by showing that G-protein-coupled formyl peptide receptors (FPRs) directly mediate neutrophil phagocytosis. Mouse neutrophils lacking formyl peptide receptors (Fpr1/2-/-) are defective in the phagocytosis of E. coli and the chemoattractant fMLP-coated beads. fMLP immobilized on the surface of a bead interacts with FPRs triggers a Ca2+ response, and induces actin polymerization to form a phagocytic cup for engulfment of the bead. Chemoattractant GPCR/Gi signaling and phagocytic receptor/tyrosine kinase signaling work independently to promote phagocytosis of beads coated with either chemoattractants or IgG opsonins. Thus, in addition to phagocytic receptor-mediated phagocytosis, neutrophils also utilize the chemoattractant GPCR/Gi signaling to mediate phagocytosis to fight invading bacteria (Wen etal, 2019). 2. Neutrophils sense and migrate through a large range of chemoattractant gradient through an adaptation mechanism. Here, we reveal CPARI, a negative regulator of Ras, that controls GPCR-stimulated Ras signaling in human neutrophils. Cells lacking CAPRI (caprikd) exhibit significantly increased phosphorylation of AKT, GSK3, and cofilin, leading to excessive actin polymerization and subsequent defects in neutrophil chemotaxis. The caprikd cells display chemotaxis defects only in high concentration, but not in low-concentration gradient, remarkably, show better chemotaxis in sub-responsive concentration of chemoattractant gradient due to their higher sensitivity. Taken together, we reveal that CAPRI controls GPCR-mediated adaptation and downshifts the sensitivity of neutrophils for Chemotaxis.