CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems.
CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems.
复制标题
CXCL14优先与稳态趋化因子受体系统协同作用。
DOI：
10.3389/fimmu.2020.561404
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发表时间：
2020
影响因子：
7.3
通讯作者：
Moser B
中科院分区：
文献类型：
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作者：
Kouzeli A;Collins PJ;Metzemaekers M;Meyrath M;Szpakowska M;Artinger M;Struyf S;Proost P;Chevigne A;Legler DF;Eberl M;Moser B
趋化因子的活性在多个水平上受到调节，包括组织和环境特异性表达以及其同源受体在靶细胞上的可用性，这反映了它们在免疫中的重要性。趋化因子协同作用，影响趋化因子和趋化因子受体的功能，已经成为一个额外的控制机制。我们之前已经证明，CXCL14是CXCR4的正变构调节剂，在多种细胞反应中能够与CXCL12协同作用。在这里，我们将我们的研究扩展到额外的稳态，以及炎症趋化因子系统的选择。我们报道，CXCL14与低（亚活性）浓度的CXCL13和CCL19/CCL21在体外趋化作用中分别与表达相应受体CXCR5和CCR7的免疫细胞强协同。通过趋化性和/或β-阻滞蛋白募集试验评估，CXCL14本身不仅对表达CXCR5或CCR7的细胞无活性，而且对表达任何其他已知的常规或非典型趋化因子受体的细胞也无活性。此外，CXCL14与炎症趋化因子CXCL10/CXCL11和CCL5之间的协同迁移反应，分别针对CXCR3和CCR5，观察到边际和偶尔的协同Ca2+通量反应。CXCL14结合到300-19细胞并干扰CCL19与表达ccr7的细胞的结合，表明这些细胞相互作用有助于报道的CXCL14介导的协同活性。我们提出了一个模型，在稳态条件下，组织表达的CXCL14有助于在稳态趋化因子显著表达的位点进行细胞定位。
Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or β-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.