The Mechanisms Involved in Chemotaxis of Immune and Cancer Cells

免疫细胞和癌细胞趋化性的机制

• 批准号: 9566738
• 负责人: Tian Jin
• 金额: $ 61.81万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9566738
• 关键词: Actins; Bacteria; Cells; Chemotactic Factors; Chemotaxis; Coupled; Defect; Escherichia coli; Exhibits; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Goals; Human; Human body; IL8 gene; Immobilization; Immune; Immunoglobulin G; Invaded; Mediating; Molecular; Mus; Natural Immunity; Neoplasm Metastasis; Opsonin; Phagocytes; Phagocytosis; Phosphorylation; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Receptor Protein-Tyrosine Kinases; Signal Transduction; Surface; Work; cancer cell; cell motility; chemokine; chemokine receptor; cofilin; fMet-Leu-Phe receptor; fighting; migration; neutrophil; polymerization; receptor; response; trafficking

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, in submission). 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.

我们有几个项目。 1. 先天免疫的一个教条是，中性粒细胞使用化学引诱剂 GPCR 通过趋化性追逐细菌，然后使用与酪氨酸激酶结合的吞噬细胞受体通过吞噬作用消灭调理的细菌。 我们目前的工作改变了这一教条，表明 G 蛋白偶联甲酰肽受体 (FPR) 直接介导中性粒细胞吞噬作用。 缺乏甲酰基肽受体 (Fpr1/2-/-) 的小鼠中性粒细胞在吞噬大肠杆菌和化学引诱剂 fMLP 包被的珠子方面存在缺陷。 固定在珠子表面的 fMLP 与 FPR 相互作用，触发 Ca2+ 反应，并诱导肌动蛋白聚合，形成吞噬杯以吞噬珠子。 趋化剂 GPCR/Gi 信号传导和吞噬细胞受体/酪氨酸激酶信号传导独立发挥作用，促进涂有趋化剂或 IgG 调理素的珠子的吞噬作用。 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剂 GPCR/Gi 信号传导介导吞噬作用来对抗入侵细菌（Wen 等人，正在提交）。 2. 中性粒细胞通过适应机制感知并迁移大范围的趋化剂梯度。在这里，我们揭示了 CPARI，Ras 的负调节因子，它控制人类中性粒细胞中 GPCR 刺激的 Ras 信号传导。缺乏 CAPRI (caprikd) 的细胞表现出 AKT、GSK3 和 cofilin 的磷酸化显着增加，导致肌动蛋白过度聚合以及随后的中性粒细胞趋化性缺陷。 Caprikd细胞仅在高浓度下表现出趋化缺陷，而在低浓度梯度下则不表现出趋化缺陷，值得注意的是，由于其较高的敏感性，在亚响应浓度的趋化剂梯度中表现出更好的趋化性。综上所述，我们发现 CAPRI 控制 GPCR 介导的适应并降低中性粒细胞趋化的敏感性。