Expression, Regulation, and Function of Atypical Chemerin Receptor CCRL2 on Endothelial Cells

Abstract

Chemokine (CC motif) receptor-like 2 (CCRL2) binds leukocyte chemoattractant chemerin and can regulate local levels of the attractant, but does not itself support cell migration. In this study, we show that CCRL2 and VCAM-1 are upregulated on cultured human and mouse vascular endothelial cells (EC) and cell lines by proinflammatory stimuli. CCRL2 induction is dependent on NF-κB and JAK/STAT signaling pathways, and activated endothelial cells specifically bind chemerin. In vivo, CCRL2 is constitutively expressed at high levels by lung endothelial cells and at lower levels by liver endothelium; and liver but not lung EC respond to systemic LPS injection by further upregulation of the receptor. Plasma levels of total chemerin are elevated in CCRL2−/− mice and are significantly enhanced after systemic LPS treatment in CCRL2−/− mice compared with wild-type mice. Following acute LPS-induced pulmonary inflammation in vivo, chemokine-like receptor 1 (CMKLR1)+ NK cell recruitment to the airways is significantly impaired in CCRL2−/− mice compared with wild-type mice. In vitro, chemerin binding to CCRL2 on endothelial cells triggers robust adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1–dependent mechanism. In conclusion, CCRL2 is expressed by EC in a tissue- and activation-dependent fashion, regulates circulating chemerin levels and its bioactivity, and enhances chemerin- and CMKLR1-dependent lymphocyte/EC adhesion in vitro and recruitment to inflamed airways in vivo. Its expression and/or induction on EC by proinflammatory stimuli provide a novel and specific mechanism for the local enrichment of chemerin at inflammatory sites, regulating the recruitment of CMKLR1+ cells.

Endothelial Cell–Derived Chemerin Promotes Dendritic Cell Transmigration

“…In addition, chemerin was reported to bind the atypical chemotactic receptor CCRL2/ACKR5 as a mechanism to concentrate bioactive chemerin on the endothelial cell surface (16,33). CCRL2 is constitutively expressed by MELC and 1G11 cells and can be further upregulated by RA and by a mixture of TNF-a, IFN-g, and LPS acting in a synergistic manner (16,33). Conceivable with CCRL2 induction, activated 1G11 endothelial cells support more efficiently than resting cells chemerininduced DC transmigration.…”

“…Chemerin is positively charged, and it is likely to bind negatively charged heparin or sulfated glycosaminoglycans expressed on the endothelial cell membranes. In addition, chemerin was reported to bind the atypical chemotactic receptor CCRL2/ACKR5 as a mechanism to concentrate bioactive chemerin on the endothelial cell surface (16,33). CCRL2 is constitutively expressed by MELC and 1G11 cells and can be further upregulated by RA and by a mixture of TNF-a, IFN-g, and LPS acting in a synergistic manner (16,33).…”

“…This mechanism is apparently tightly regulated. First, the activation of TLRs by infectious or autoimmune stimuli is responsible for the upregulation of inflammatory cytokines that will induce the production of RA by aldehyde dehydrogenase-expressing DC and the upregulation of CCRL2 in endothelial cells (33,38). Second, RA will further upregulate the expression of CCRL2 and the production of prochemerin by activated endothelial cells.…”

“…Recently, it was reported that the atypical chemotactic receptor CCRL2 binds and concentrates chemerin at the endothelial cell surface (33). Therefore, it was investigated whether a similar mechanism could function in mouse vascular 1G11 endothelial cells.…”

La chémérine

“…Enfin, CCRL2 n'induit pas de signalisation intracellulaire connue à ce jour [17,18]. Ce récepteur est fortement exprimé dans les cellules endothéliales du poumon et plus faiblement au niveau du foie [19]. Il pourrait réguler la biodisponibilité de la chémérine en la séquestrant et en la présentant au récepteur CMKLR1 présent sur des cellules voisines [18].…”