Abstract
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.
Highlights
CXCL14 is one of the least understood chemokines, featuring remarkable amino acid sequence conservation across a wide range of species and constitutive expression in border-lining tissues by epithelial cells, fibroblasts and macrophages [1]
We report that CXCL14 did not activate any of the known classical or atypical chemokine receptors but exhibited synergistic responses with the homeostatic chemokines CXCL13, CCL19 and CCL21 in inducing the chemotactic migration of cells expressing the corresponding chemokine receptors CXCR5 and CCR7
The most robust and reproducible synergistic responses were seen during in vitro chemotaxis assays, the prototypical test for defining the functionality and target cell specificity of chemokines. Based on these results we conclude that CXCL14 preferentially synergizes with the major homeostatic chemokines involved in controlling steady-state processes as diverse as immune surveillance of secondary lymphoid tissues (CXCL13, CCL19, CCL21) and tissue development (CXCL12) [42, 43]
Summary
CXCL14 is one of the least understood chemokines, featuring remarkable amino acid sequence conservation across a wide range of species and constitutive expression in border-lining tissues by epithelial cells, fibroblasts and macrophages [1]. Induction of Ca2+ mobilization and sensitivity to Bordetella pertussis toxin treatment in monocytes suggests that the elusive CXCL14 receptor is a prototypical chemokine receptor that requires Gα i-type G-proteins for signaling [3]. CXCL14 does not belong to the subset of chemokines whose expression is induced only under inflammatory conditions. Inflammatory stimuli (LPS, TNF-α, ROS) and growth factors (VEGF, EGF) that signal through the MEK/ERK pathway were shown to inhibit the constitutive expression of CXCL14 [7,8,9,10], an effect frequently linked with epigenetic silencing [8, 11,12,13,14]. Positive modulators of CXCL14 expression are less clear and vary depending on the cellular context [15,16,17]
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