Immune responses highly depend on the effective trafficking of immune cells into and within secondary lymphoid organs (SLOs). Atypical chemokine receptors (ACKRs) scavenge chemokines to eliminate them from the extracellular space, thereby generating gradients that guide leukocytes. In contrast to canonical chemokine receptors, ACKRs do not induce classical intracellular signaling that results in cell migration. Recently, the closest relative of ACKR3, GPR182, has been partially deorphanized as a potential novel ACKR. We confirm and extend previous studies by identifying further ligands that classify GPR182 as a broadly scavenging chemokine receptor. We validate the “atypical” nature of the receptor, wherein canonical G-protein-dependent intracellular signaling is not activated following ligand stimulation. However, β-arrestins are required for ligand-independent internalization and chemokine scavenging whereas the C-terminus is in part dispensable. In the absence of GPR182 in vivo, we observed elevated chemokine levels in the serum but also in SLO interstitium. We also reveal that CXCL13 and CCL28, which do not bind any other ACKR, are bound and efficiently scavenged by GPR182. Moreover, we found a cooperative relationship between GPR182 and ACKR3 in regulating serum CXCL12 levels, and between GPR182 and ACKR4 in controlling CCL20 levels. Furthermore, we unveil a new phenotype in GPR182-KO mice, in which we observed a reduced marginal zone (MZ), both in size and in cellularity, and thus in the T-independent antibody response. Taken together, we and others have unveiled a novel, broadly scavenging chemokine receptor, which we propose should be named ACKR5.

中文翻译：

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GPR182 是一种广泛清除非典型趋化因子受体，影响 T 独立免疫

免疫反应高度依赖于免疫细胞有效转运至次级淋巴器官 (SLO) 内。非典型趋化因子受体（ACKR）清除趋化因子，将其从细胞外空间消除，从而产生引导白细胞的梯度。与经典趋化因子受体相比，ACKR 不会诱导导致细胞迁移的经典细胞内信号传导。最近，ACKR3 的最近亲 GPR182 已被部分去孤儿化，成为一种潜在的新型 ACKR。我们通过鉴定将 GPR182 分类为广泛清除趋化因子受体的进一步配体，确认并扩展了之前的研究。我们验证了受体的“非典型”性质，其中典型的 G 蛋白依赖性细胞内信号传导在配体刺激后不会被激活。然而，β-抑制蛋白是配体依赖性内化和趋化因子清除所必需的，而 C 末端部分是可有可无的。在没有 GPR182 的情况下体内，我们观察到血清中以及 SLO 间质中的趋化因子水平升高。我们还揭示了不结合任何其他 ACKR 的 CXCL13 和 CCL28 被 GPR182 结合并有效清除。此外，我们发现GPR182和ACKR3在调节血清CXCL12水平方面以及GPR182和ACKR4在控制CCL20水平方面存在协同关系。此外，我们在 GPR182-KO 小鼠中揭示了一种新的表型，其中我们观察到边缘区 (MZ) 的大小和细胞结构均减少，因此 T 依赖性抗体反应也减少。总之，我们和其他人共同揭示了一种新型的、广泛清除趋化因子受体，我们建议将其命名为 ACKR5。