Inhibition of CXCR3‐mediated chemotaxis by the human chemokine receptor‐like protein CCX‐CKR

Abstract

Background and Purpose Induction of cellular migration is the primary effect of chemokine receptor activation. However, several chemokine receptor‐like proteins bind chemokines without subsequent induction of intracellular signalling and chemotaxis. It has been suggested that they act as chemokine scavengers, which may control local chemokine levels and contribute to the function of chemokines during inflammation. This has been verified for the chemokine‐like receptor proteins D6 and DARC as well as CCX‐CKR. Here, we provide evidence for an additional biological function of human (h)CCX‐CKR. Experimental Approach We used transfection strategies in HEK293 and human T cells. Key Results Co‐expression of hCCX‐CKR completely inhibits hCXCR3‐induced chemotaxis. We found that hCCX‐CKR forms complexes with hCXCR3, suggesting a relationship between CCX‐CKR heteromerization and inhibition of chemotaxis. Moreover, negative binding cooperativity induced by ligands both for hCXCR3 and hCCX‐CKR was observed in cells expressing both receptors. This negative cooperativity may also explain the hCCX‐CKR‐induced inhibition of chemotaxis. Conclusions and Implications These findings suggest that hCCX‐CKR prevents hCXCR3‐induced chemotaxis by heteromerization thus representing a novel mechanism of regulation of immune cell migration.

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…Accordingly, it is reasonable to speculate that DARC may also form complexes with the CXCR2 receptor and, consequently, prevents its binding to CXCL1. However, in the aforementioned study, the investigators did not find any difference in CXCR3 expression in HEK293 cells, whether or not they were cotransfected with CCX-CKR (63). In contrast, we observed an increase in CXCR2 protein expression in DARC-deficient ASMCs upon treatment with CXCL1, suggesting that the presence of DARC may have a regulatory influence on CXCR2 expression.…”

“…However, it was not able to bind to CXCR2 on neutrophils (62), suggesting the possibility that DARC may compete with CXCR2 for the binding of CXCL1. In addition, CCX-CKR, another decoy receptor, was reported to inhibit CXCR3-mediated chemotaxis of cotransfected HEK293 cells by forming heterodimeric complexes with CXCR3 and subsequently affecting its binding properties (63). Accordingly, it is reasonable to speculate that DARC may also form complexes with the CXCR2 receptor and, consequently, prevents its binding to CXCL1.…”

Overview and potential unifying themes of the atypical chemokine receptor family

“…ACKRs have also been reported to interfere with the signaling pathways of coexpressed conventional chemokine receptors, indicating that their regulatory activity may not be restricted to receptors with shared ligands but also applies to receptors coexpressed on the same cell. Examples are provided by ACKR2 interfering with CXCR5 signaling on B lymphocytes [24] and ACKR4 interfering with CXCR3 signaling on T lymphocytes [124]. Finally, it has to be noted that ACKR expression on different cell contexts may correspond to different functional properties, as exemplified by ACKR1, which acts as a sink on erythrocytes and as a transporter on endothelial cells [62].…”

“…2A). All ACKRs but not ACKR4 have been demonstrated to be able to interfere with signaling properties of conventional receptors through direct binding of cognate ligands, and ACKR1, ACKR3, and ACKR4 have also been shown to form oligomers with conventional chemokine receptors [122,124,132,133]. Coexpression of ACKR1 results in impaired CCR5-mediated signaling and chemotaxis properties [122], ACKR2 impairs CCR4-mediated chemotaxis [134], ackr5 impairs CCR7-dependent activation of B cells [123] and dendritic cell chemotaxis [47], and ACKR3 alters CXCR3 [135], as well as signaling properties of CD74 (the other MIF receptor) [13] and AM receptor [32].…”

The Role of Atypical Chemokine Receptor CCXCKR (CCRL1) in Human Diseases

“…They efficiently affect the function of typical chemokine receptors by the internalization and degradation of chemokines. 1 That is why they are called scavenger proteins, decoy, intercepting receptors, and silent receptors.…”