The Mechanisms Involved in Chemotaxis of Immune and Cancer Cells

免疫细胞和癌细胞趋化性的机制

基本信息

批准号：
10927866
负责人：
Tian Jin
金额：
$ 71.48万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

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.

我们几个项目。 1。先天免疫的教条是，中性粒细胞使用化学吸引剂GPCR通过趋化性追逐细菌，然后使用吞噬受体与酪氨酸激酶结合的吞噬受体通过吞噬作用来破坏调子细菌。我们目前的工作通过表明G蛋白偶联的甲基肽受体（FPRS）直接介导中性粒细胞吞噬作用来改变这一教条。缺乏甲基肽受体（FPR1/2 - / - ）的小鼠中性粒细胞在大肠杆菌的吞噬作用和化学吸引剂FMLP涂有珠的吞噬作用中有缺陷。固定在珠子表面的FMLP与FPRS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。化学吸引剂GPCR/GPCR信号传导和吞噬受体/酪氨酸激酶信号传导独立地促进涂有趋化剂或IgG opsonins涂有珠的吞噬作用。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剂GPCR/GI信号传导介导吞噬作用以对抗入侵细菌（Wen etal，2019）。 2。中性粒细胞通过适应机制感知并通过大量的趋化梯度迁移。在这里，我们揭示了CPARI是RAS的负调节剂，该CPARI控制了人类中性粒细胞中GPCR刺激的RAS信号传导。缺乏CAPRI（CAPRIKD）的细胞显示出Akt，GSK3和Cofilin的磷酸化显着增加，导致过度肌动蛋白聚合和随后的中性粒细胞趋化性缺陷。 Caprikd细胞仅在高浓度下显示出趋化性缺陷，但在低浓度梯度中不显示出明显的趋化梯度，由于其较高的敏感性，在趋化剂梯度的亚反应性浓度中显示了更好的趋化性。综上所述，我们揭示了Capri控制GPCR介导的适应性，并降档中性粒细胞对趋化性的敏感性。