Institute of Biology Leiden, Leiden University, Leiden, Netherlands.
Front Immunol. 2020 Feb 25;11:325. doi: 10.3389/fimmu.2020.00325. eCollection 2020.
Phagocytes are highly motile immune cells that ingest and clear microbial invaders, harmful substances, and dying cells. Their function is critically dependent on the expression of chemokine receptors, a class of G-protein-coupled receptors (GPCRs). Chemokine receptors coordinate the recruitment of phagocytes and other immune cells to sites of infection and damage, modulate inflammatory and wound healing responses, and direct cell differentiation, proliferation, and polarization. Besides, a structurally diverse group of atypical chemokine receptors (ACKRs) are unable to signal in G-protein-dependent fashion themselves but can shape chemokine gradients by fine-tuning the activity of conventional chemokine receptors. The optically transparent zebrafish embryos and larvae provide a powerful system to visualize phagocytes during development and study them as key elements of the immune response in real-time. In this review, we discuss how the zebrafish model has furthered our understanding of the role of two main classes of chemokine receptors, the CC and CXC subtypes, in phagocyte biology. We address the roles of the receptors in the migratory properties of phagocytes in zebrafish models for cancer, infectious disease, and inflammation. We illustrate how studies in zebrafish enable visualizing the contribution of chemokine receptors and ACKRs in shaping self-generated chemokine gradients of migrating cells. Taking the functional antagonism between two paralogs of the CXCR3 family as an example, we discuss how the duplication of chemokine receptor genes in zebrafish poses challenges, but also provides opportunities to study sub-functionalization or loss-of-function events. We emphasize how the zebrafish model has been instrumental to prove that the major determinant for the functional outcome of a chemokine receptor-ligand interaction is the cell-type expressing the receptor. Finally, we highlight relevant homologies and analogies between mammalian and zebrafish phagocyte function and discuss the potential of zebrafish models to further advance our understanding of chemokine receptors in innate immunity and disease.
吞噬细胞是高度运动的免疫细胞，可吞噬和清除微生物入侵物、有害物质和死亡细胞。它们的功能取决于趋化因子受体的表达，趋化因子受体是一类 G 蛋白偶联受体（GPCR）。趋化因子受体协调吞噬细胞和其他免疫细胞向感染和损伤部位的募集，调节炎症和伤口愈合反应，并指导细胞分化、增殖和极化。此外，一组结构多样的非典型趋化因子受体（ACKR）本身不能以 G 蛋白依赖的方式发出信号，但可以通过微调传统趋化因子受体的活性来精细调节趋化因子梯度。光学透明的斑马鱼胚胎和幼虫为可视化发育过程中的吞噬细胞并实时研究它们作为免疫反应关键元件的系统提供了强大的工具。在这篇综述中，我们讨论了斑马鱼模型如何进一步了解 CC 和 CXC 两种主要趋化因子受体亚型在吞噬细胞生物学中的作用。我们研究了这些受体在斑马鱼癌症、感染性疾病和炎症模型中吞噬细胞迁移特性中的作用。我们举例说明了在斑马鱼中进行的研究如何使我们能够可视化趋化因子受体和 ACKR 对迁移细胞自身产生的趋化因子梯度的贡献。以 CXCR3 家族两个平行基因的功能拮抗作用为例，我们讨论了趋化因子受体基因在斑马鱼中的重复如何带来挑战，但也为研究亚功能化或功能丧失事件提供了机会。我们强调了斑马鱼模型如何有助于证明趋化因子受体-配体相互作用的功能结果的主要决定因素是表达受体的细胞类型。最后，我们强调了哺乳动物和斑马鱼吞噬细胞功能之间的相关性和相似性，并讨论了斑马鱼模型在深入了解先天免疫和疾病中的趋化因子受体方面的潜在应用。
