Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4

Abstract

The chemokine receptor, CXC chemokine receptor 4 (CXCR4), is selective for CXC chemokine ligand 12 (CXCL12), is broadly expressed in blood and tissue cells, and is essential during embryogenesis and hematopoiesis. CXCL14 is a homeostatic chemokine with unknown receptor selectivity and preferential expression in peripheral tissues. Here, we demonstrate that CXCL14 synergized with CXCL12 in the induction of chemokine responses in primary human lymphoid cells and cell lines that express CXCR4. Combining subactive concentrations of CXCL12 with 100–300 nM CXCL14 resulted in chemotaxis responses that exceeded maximal responses that were obtained with CXCL12 alone. CXCL14 did not activate CXCR4-expressing cells (i.e., failed to trigger chemotaxis and Ca2+ mobilization, as well as signaling via ERK1/2 and the small GTPase Rac1); however, CXCL14 bound to CXCR4 with high affinity, induced redistribution of cell-surface CXCR4, and enhanced HIV-1 infection by >3-fold. We postulate that CXCL14 is a positive allosteric modulator of CXCR4 that enhances the potency of CXCR4 ligands. Our findings provide new insights that will inform the development of novel therapeutics that target CXCR4 in a range of diseases, including cancer, autoimmunity, and HIV.—Collins, P. J., McCully, M. L., Martínez-Muñoz, L., Santiago, C., Wheeldon, J., Caucheteux, S., Thelen, S., Cecchinato, V., Laufer, J. M., Purvanov, V., Monneau, Y. R., Lortat-Jacob, H., Legler, D. F., Uguccioni, M., Thelen, M., Piguet, V., Mellado, M., Moser, B. Epithelial chemokine CXCL14 synergizes with CXCL12 via allosteric modulation of CXCR4.

Infectious Laryngotracheitis Virus Viral Chemokine-Binding Protein Glycoprotein G Alters Transcription of Key Inflammatory Mediators In Vitro and In Vivo

“…Both CXCL12 and CXCL14 are chemoattractants for distinct populations of cells that are recruited to the trachea and affected by the presence of gG (8), where CXCL14 is associated with neutrophil chemotaxis in mammals (31), while CXCL12 is involved in the trafficking of B cells (32) and the recruitment of naive CD4 ϩ and CD8 ϩ T cells (33,34). Future studies to examine the interactions between chicken CXCL12 and CXCL14 and the CXCR4 receptor (35), as well as between chCXCLi1 and chCXCLi2 and the CXCR1 receptor, in the presence or absence of gG are warranted. Such studies (36) have proven to be very useful for providing a better understanding of the chemotactic role of HSV gG.…”

High‐mobility group box 1 protein orchestrates responses to tissue damage via inflammation, innate and adaptive immunity, and tissue repair

“…Fully reduced HMGB1 (also called all‐thiol‐HMGB1) forms a heterocomplex with the chemokine CXCL12, and the HMGB1‐CXCL12 heterocomplex binds CXCR4, a 7‐transmembrane G‐protein‐coupled receptor (GPCR) . CXCR4 forms dimers, multimers, and heterodimers with other GPCR receptors and binds several ligands, including CXCL12, CXCL14, the HMGB1‐CXCL12 heterocomplex, MIF, extracellular ubiquitin, and viral proteins . Different ligands induce different conformations of CXCR4, which determine the balance of several signaling pathways downstream, including G proteins and calcium pathways, beta‐arrestins and JAK, GRK, MAPK, and PI3K kinases.…”

Peripheral Tissue Chemokines: Homeostatic Control of Immune Surveillance T Cells

“…Similar to CXCL12, CXCL14 is involved in tissue development and glucose metabolism that may explain, in part, the striking survival defects observed in CXCL14-KO mice [70][71][72]. It is a chemoattractant for myeloid cells, 20 notably blood monocytes, and also synergizes with CXCL12 in CXCR4-mediated chemokine responses [73]. Slow progress in CXCL14 research is largely due to the fact that its receptor has remained elusive.…”