Expression, regulation, and function of atypical chemerin receptor CCRL2 on endothelial cells.
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 α(4)β(1) 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.
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Justin
J
Monnier
Susanna
S
Lewén
Edward
E
O'Hara
Kexin
K
Huang
Hua
H
Tu
Eugene C
EC
Butcher
Brian A
BA
Zabel
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines; D002630:Chemotactic Factors / Q000097:blood; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D053612:Janus Kinases / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D054388:Receptors, CCR / Q000096:biosynthesis* / Q000172:deficiency / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
C487531:CCRL2 protein, human; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D054388:Receptors, CCR; D050791:STAT Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; C523686:chemerin protein, mouse; D053612:Janus Kinases