Abstract
Activated platelets release micromolar concentrations of the chemokine CXCL4/Platelet Factor-4. Deposition of CXCL4 onto the vascular endothelium is involved in atherosclerosis, facilitating monocyte arrest and recruitment by an as yet, unidentified receptor. Here, we demonstrate that CXCL4 drives chemotaxis of the monocytic cell line THP-1. Migration and intracellular calcium responses induced by CXCL4 were pertussis toxin-sensitive, implicating a GPCR in signal transduction. Cell treatment with chondroitinase ABC ablated migration, suggesting that cis presentation of CXCL4 by cell surface glycosaminoglycans to a GPCR is required. Although CXCR3 has been previously described as a CXCL4 receptor, THP-1 cells were unresponsive to CXCR3 ligands and CXCL4-induced migration was insensitive to a CXCR3 antagonist, suggesting that an alternative receptor is involved. Interrogating CC-class chemokine receptor transfectants, we unexpectedly found that CXCL4 could induce the migration of CCR1-expressing cells and also induce CCR1 endocytosis. Extending our findings to primary human monocytes, we observed that CXCL4 induced CCR1 endocytosis and could induce monocyte chemotaxis in a CCR1 antagonist-sensitive manner. Collectively, our data identify CCR1 as a previously elusive monocyte CXCL4 receptor and suggest that CCR1 may play a role in inflammation where the release of CXCL4 is implicated.
Highlights
Chemokines represent a large family of small peptides that typically signal via G protein-coupled receptors (GPCRs) and which recruit leukocytes to inflammatory sites and lymphoid microenvironments[1]
In this study we provide several clear lines of evidence to demonstrate that CXCL4 is an agonist of the CC chemokine receptor CCR1 and that this receptor mediates CXCL4-signaling in human monocytes
No migration of THP-1 cells to the CXCR3 ligands CXCL10 and CXCL11 was observed (Fig. 1A), nor could we detect significant levels of cell surface CXCR3 expression with a specific antibody nor specific binding of radiolabeled CXCL10 (Supplementary Fig. 1). This suggests that in contrast to CXCL4 signaling in T cells[17,18], CXCL4 responses in THP-1 cells are not mediated by either of the CXCR3 variants
Summary
Chemokines represent a large family of small peptides that typically signal via G protein-coupled receptors (GPCRs) and which recruit leukocytes to inflammatory sites and lymphoid microenvironments[1]. There is some debate as to whether or not CXCL4 alone is able to induce monocyte migration[12,13], CXCL4 has been shown to form functional heterodimers with CC chemokines such as CCL5/RANTES that promote monocyte arrest on endothelium[14] These CXCL4/CCL5 heterodimers are atherogenic, since inhibition of their formation by small molecule antagonists is protective in a mouse model of atherosclerosis[15]. In this study we provide several clear lines of evidence to demonstrate that CXCL4 is an agonist of the CC chemokine receptor CCR1 and that this receptor mediates CXCL4-signaling in human monocytes. This has implications for its targeting in the treatment of atherosclerosis and other inflammatory diseases
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