Abstract
C-C chemokine receptor-like 2 (CCRL2) is a non-signaling seven-transmembrane domain (7-TMD) receptor related to the atypical chemokine receptor (ACKR) family. ACKRs bind chemokines but do not activate G protein-dependent signaling or cell functions. ACKRs were shown to regulate immune functions in vivo by their ability to scavenge chemokines from the local environment. This study was performed to investigate whether CCRL2 shares two of the main characteristics of ACKRs, namely the ability to internalize and scavenge the ligands. Cell membrane analysis of CCRL2-transfected cells revealed a weak, constitutive, ligand-independent internalization, and recycling of CCRL2, with a kinetics that was slower than those observed with ACKR3, a prototypic ACKR, or other chemotactic signaling receptors [i.e., chemokine-like receptor 1 and C-X-C motif chemokine receptor 2]. Intracellularly, CCRL2 colocalized with early endosome antigen 1-positive and Rab5-positive vesicles and with recycling compartments mainly characterized by Rab11-positive vesicles. CCRL2-transfected cells and activated mouse blood endothelial cells, that endogenously express CCRL2, were used to investigate the scavenging ability of CCRL2. These experiments confirmed the ability of CCRL2 to bind chemerin, the only recognized ligand, but excluded the ability of CCRL2 to perform scavenging. Collectively, these results identify unique functional properties for this member of the non-signaling 7-TMD receptor family.
Highlights
Chemokines are soluble mediators that regulate immune functions and development, mainly through their ability to promote leukocyte trafficking
To study the intracellular trafficking, acyl carrier protein (ACP)tagged chemokine receptor like 2 (CCRL2) was expressed in HeLa cells and receptors were enzymatically labeled using a fluorescent dye
Since atypical chemokine receptor (ACKR) are characterized by rapid constitutive internalization [33,34,35], the kinetics of CCRL2 internalization was compared to that of ACKR3, a receptor belonging to the ACKR family [34], and to that of two chemotactic receptors, namely C-X-C motif chemokine receptor 2 (CXCR2) and chemokinelike receptor 1 (CMKLR1)
Summary
Chemokines are soluble mediators that regulate immune functions and development, mainly through their ability to promote leukocyte trafficking. CCRL2 Is Not a Scavenger Receptor (ACKRs) [1]. ACKRs do not signal through G proteins, but rather they promote ligand internalization and degradation. ACKRs can transport the ligand across the cell [2]. By these mechanisms, ACKRs were shown to regulate chemokine availability, shape the chemokine gradient and regulate inflammatory responses in vivo [2,3,4,5]. An additional 7-TMD receptor, called C-C chemokine receptor like 2 (CCRL2), was proposed as the fifth member of the ACKR family, pending confirmation of its ability to bind chemokines [1]
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