CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)–based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.

中文翻译：

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CXCL17 是一种 CXCR4 的变构抑制剂，其作用机制涉及糖胺聚糖

CXCL17 是一种主要由粘膜组织表达的趋化因子，可促进单核细胞、树突状细胞和巨噬细胞的趋化性，并具有抗菌特性。 CXCL17 还与炎症性疾病的病理学和多种癌症的进展有关，并且其表达在肺部病毒感染期间增加。然而，CXCL17在健康和疾病中的确切作用需要进一步研究，并且需要确认介导CXCL17功能反应的分子靶点。使用一系列基于生物发光共振能量转移 (BRET) 的检测，我们证明 CXCL17 抑制 CXCR4 介导的信号传导和配体结合。此外，CXCL17 与 Neuropillin-1（一种 VEGFR2 辅助受体）相互作用。此外，我们发现 CXCL17 仅抑制完整细胞中的 CXCR4 配体结合，并证明已知的糖胺聚糖结合剂、surfen 和硫酸鱼精蛋白可以模仿这种效应。 CXCL17 中假定的 GAG 结合域的破坏阻止了 CXCR4 的结合。这表明 CXCL17 通过一种可能需要含有糖胺聚糖的辅助蛋白存在的作用机制来抑制 CXCR4。总之，我们的结果表明 CXCL17 是 CXCR4 的内源性抑制剂，代表着我们对 CXCL17 功能和 CXCR4 信号传导调节的理解又向前迈进了一步。