In the human chemokine system, interactions between the approximately 50 known endogenous chemokine ligands and 20 known chemokine receptors (CKRs) regulate a wide range of cellular functions and biological processes including immune cell activation and homeostasis, development, angiogenesis, and neuromodulation. CKRs are a family of G protein-coupled receptors (GPCR), which represent the most common and versatile class of receptors in the human genome and the targets of approximately one third of all Food and Drug Administration-approved drugs. Chemokines and CKRs bind with significant promiscuity, as most CKRs can be activated by multiple chemokines and most chemokines can activate multiple CKRs. While these ligand-receptor interactions were previously regarded as redundant, it is now appreciated that many chemokine:CKR interactions display biased agonism, the phenomenon in which different ligands binding to the same receptor signal through different pathways with different efficacies, leading to distinct biological effects. Notably, these biased responses can be modulated through changes in ligand, receptor, and or the specific cellular context (system). In this review, we explore the biochemical mechanisms, functional consequences, and therapeutic potential of biased agonism in the chemokine system. An enhanced understanding of biased agonism in the chemokine system may prove transformative in the understanding of the mechanisms and consequences of biased signaling across all GPCR subtypes and aid in the development of biased pharmaceuticals with increased therapeutic efficacy and safer side effect profiles.

在人类趋化因子系统中，大约 50 种已知的内源性趋化因子配体和 20 种已知的趋化因子受体 (CKR) 之间的相互作用调节广泛的细胞功能和生物学过程，包括免疫细胞激活和体内平衡、发育、血管生成和神经调节。CKR 是 G 蛋白偶联受体 (GPCR) 家族，它代表了人类基因组中最常见和最通用的受体类别，也是美国食品和药物管理局批准的所有药物中大约三分之一的靶标。趋化因子和 CKR 结合具有显着的混杂性，因为大多数 CKR 可以被多种趋化因子激活，并且大多数趋化因子可以激活多个 CKR。虽然这些配体-受体相互作用以前被认为是多余的，但现在人们认识到许多趋化因子：CKR 相互作用显示偏向激动，即不同的配体通过不同的途径以不同的功效与同一受体信号结合，从而产生不同的生物学效应的现象。值得注意的是，这些有偏见的反应可以通过配体、受体和/或特定细胞环境（系统）。在这篇综述中，我们探讨了趋化因子系统中偏向激动的生化机制、功能后果和治疗潜力。加深对趋化因子系统中偏向激动的理解可能会在理解所有 GPCR 亚型中偏向信号传导的机制和后果方面具有变革性，并有助于开发具有更高治疗效果和更安全副作用的偏向药物。