CCRL2 | Chemokine receptors | IUPHAR/BPS Guide to PHARMACOLOGY

CCRL2

Target id: 78

Nomenclature: CCRL2

Family: Chemokine receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     CCRL2 has curated GtoImmuPdb data

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 344 3p21 CCRL2 C-C motif chemokine receptor like 2
Mouse 7 360 9F Ccrl2 chemokine (C-C motif) receptor-like 2
Rat 7 423 8q32 Ccrl2 C-C motif chemokine receptor like 2
Previous and Unofficial Names
CCR11 | CKRX | CRAM-A | CRAM-B | ACR5 | CCR6 | Chemokine receptor X
Database Links
Specialist databases
GPCRDB ccrl2_human (Hs), ccrl2_mouse (Mm), d3zvm9_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
CCL19 {Sp: Human} , CCL19 {Sp: Mouse}
Endogenous ligands (Human)
chemerin C-terminal peptide, CCL19 (CCL19, Q99731)  [3]

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CCL19 {Sp: Human} Hs Unknown 7.4 pIC50 15
pIC50 7.4 [15]
Agonist Comments
Stimulation by CCL19 does not result in typical chemokine-receptor-dependent cellular activation (e.g. calcium mobilization or migration) [15,24-25]. Biotinylated CCL2 binds to CCRL2-expressing HEK293 cells, although radioligand binding was not detected [4,26]. Chemerin blocked the binding of anti-mCCRL2 antibody to mouse peritoneal mast cells, but despite binding to the N-terminal domain of mCCRL2 with high affinity, chemerin elicited no functional response. CCRL2 appears to concentrate bioactive chemerin and facilitate its presentation to ChemR23 on adjacent cells [23,25]. Binding of chemerin to CCRL2 has been demonstrated to trigger adhesion of CMKLR1+ lymphoid cells through an α4β1 integrin/VCAM-1–dependent mechanism therefore CCRl2 plays a role in chemerin-dependent lymphocyte recruitment to inflamed airways, and the regulation of circulating chemerin levels [17].
Immunopharmacology Comments
CCRL2 is one of more than 20 distinct chemokine receptors expressed in human leukocytes. Chemokines primarily act to promote leukocyte chemotaxis to sites of inflammation. However, the nomenclature of CCLR2 for this receptor and its classification as a member of the chemokine receptor family is provisional pending confirmation of chemokine binding.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0006954 inflammatory response ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0004950 chemokine receptor activity TAS
Tissue Distribution
Spleen, fetal liver, lymph nodes, bone marrow, lung, heart, thymus, placenta
Species:  Human
Technique:  Northern blot
References:  10
Leukocytes
Species:  Human
Technique:  Immunocytochemistry
References:  11
LPS activated macrophages
Species:  Mouse
Technique:  Northern blot
References:  21
Astrocytes, microglia (upregulated after stimulation with LPS)
Species:  Mouse
Technique:  RT-PCR
References:  26
Mast cells
Species:  Mouse
Technique:  Immunohistochemistry
References:  23,25
Activated dendritic cells, macrophages. No expression in eosinophils, T cells
Species:  Mouse
Technique:  Northern blot
References:  20
Tissue Distribution Comments
CCRL2 surface expression on the pre-B-cell lines Nalm6 and G2 is specifically upregulated in response to the inflammatory chemokine CCL5 (RANTES) [12]. CCRL2 mRNA and protein was rapidly (30 minutes) and transiently (2-4 hours) regulated during dendritic cell maturation [20]. CCRL2 mRNA expression is strongly upregulated in mouse lung after ovalbumin challenge and is localised in macrophages and bronchial epithelium, as shown by immunohistochemistry [19].
Physiological Functions
Control of excessive airway inflammatory response
Species:  Mouse
Tissue:  Dentritic cells (lung)
References:  20
Physiological Consequences of Altering Gene Expression
CCRL2-deficient mice had significantly reduced passive cutaneous anaphylaxis reactions when a low sensitizing dose of DNP-specific IgE was used (50 ng/ear), suggesting that mCCRL2 ligation normally amplifies the inflammatory response.
Species:  Mouse
Tissue:  Mast cells
Technique:  Gene knockout
References:  23,25
Defective trafficking of antigen-loaded lung dendritic cells to mediastinal lymph nodes in CCRL2 knockout mice, associated with a reduction in lymph node cellularity and reduced priming of T helper cell 2 response
Species:  None
Tissue:  Dendritic cells
Technique:  Gene knockout
References:  20
Physiological Consequences of Altering Gene Expression Comments
CCRL2 mRNA levels are significantly higher in db/db mouse white adipose tissue, and there is a trend towards increased expression in ob/ob mice, compared to control [9].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0010740 abnormal dendritic cell chemotaxis PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0002148 abnormal hypersensitivity reaction PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0005466 abnormal T-helper 2 physiology PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0008673 decreased interleukin-13 secretion PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0008700 decreased interleukin-4 secretion PMID: 20606167 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0008703 decreased interleukin-5 secretion PMID: 20606167 
Ccrl2tm1Lex Ccrl2tm1Lex/Ccrl2tm1Lex
involves: 129S/SvEvBrd * C57BL/6
MGI:1920904  MP:0005597 decreased susceptibility to type I hypersensitivity reaction PMID: 18794339 
Ccrl2tm1Ssoz Ccrl2tm1Ssoz/Ccrl2tm1Ssoz
B6.129-Ccrl2
MGI:1920904  MP:0008101 lymph node hypoplasia PMID: 20606167 
Ccrl2tm1Dgen Ccrl2tm1Dgen/Ccrl2tm1Dgen
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:1920904  MP:0002169 no abnormal phenotype detected
Clinically-Relevant Mutations and Pathophysiology
Disease:  Pneumocystis pneumonia
Disease Ontology: DOID:11339
Role: 
References:  1
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human F167Y Single nucleotide polypmorpism resulting in non-conservative amino acid substitution 1
Disease:  Rheumatoid arthritis
Disease Ontology: DOID:7148
OMIM: 180300
Role: 
References:  2,11
Clinically-Relevant Mutations and Pathophysiology Comments
Three single-nucleotide polymorphisms (rs1154428, rs6808835, and rs6791599) in CCRL2 in linkage disequilibrium with CCR5Delta32 are associated with high-density lipoprotein cholesterol in at risk cardiovascular patients, suggesting that chemokine activity influences lipid levels in populations with preexisting cardiovascular disease [13].
Gene Expression and Pathophysiology
CCRL2 expression is seen in the spinal cord and brain (predominantly astrocytes and microglia) of mice with experimental autoimmune encephalomyelitis
Tissue or cell type:  Spinal cord and brain
Pathophysiology:  Autoimmune encephalomyelitis
Species:  Mouse
Technique:  PCR, in situ hybridisation and immunohistochemistry
References:  5
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  I255V
Global MAF (%):  5
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 3|4|10
Minor allele count:  G=0.051/111
SNP accession: 
Validation:  Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  M1I
Global MAF (%):  5
Subpopulation MAF (%):  AFR: 19
Minor allele count:  A=0.046/101
SNP accession: 
Validation:  Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R5H
Global MAF (%):  6
Subpopulation MAF (%):  AMR|AFR: 1|25
Minor allele count:  A=0.0595/130
SNP accession: 
Validation:  Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  W16C
Global MAF (%):  1
Subpopulation MAF (%):  AMR|EUR: 1|2
Minor allele count:  G=0.010/21
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  F179W
Global MAF (%):  37
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 11|40|53|40
Minor allele count:  A=0.370/808
SNP accession: 
Validation:  Frequency
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  V180M
Global MAF (%):  9
Subpopulation MAF (%):  AFR|AMR|EUR: 12|13|13
Minor allele count:  A=0.095/207
SNP accession: 
Validation:  Frequency
Type:  Naturally occurring SNPs
Species:  Human
Description:  Intron variant which may be associated with AIDS progression. This polymorphism has a global MAF of 21% (4% AFR, 22% AMR, 21% ASN, 30% EUR)
SNP accession: 
References:  22
Biologically Significant Variant Comments
Human CCRL2 has two splice variants: CCRL2A (Acc. NM_003965) and CCRL2B (Acc. NM_001130910). Variant B encodes the predominant isoform, which is localized at the plasma membrane. It is alternatively spliced within the coding region and thus uses an earlier stop codon, as compared with the isoform A. Variant B has a distinct C-terminus and is 14 aa shorter than the isoform A [14]. Splice variants are differentially expressed in B-cells dependent on maturation stage [12].
General Comments
A study of the haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes reveals a cluster of four CC-chemokine receptor genes (CCR3, CCR2, CCR5 and CCRL2) on chromosome 3p21 [6-7]. CCRL2 neither internalizes its ligands nor transduces signals, but presents bound ligands to functional signaling receptors improving their activity [16,18].

CCRL2-predicted hepatitis C treatment response to pegylated interferon and ribavirin therapy has been verified by RT-qPCR [8].

References

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1. An P, Li R, Wang JM, Yoshimura T, Takahashi M, Samudralal R, O'Brien SJ, Phair J, Goedert JJ, Kirk GD et al.. (2011) Role of exonic variation in chemokine receptor genes on AIDS: CCRL2 F167Y association with pneumocystis pneumonia. PLoS Genet., 7 (10): e1002328. [PMID:22046140]

2. Auer J, Bläss M, Schulze-Koops H, Russwurm S, Nagel T, Kalden JR, Röllinghoff M, Beuscher HU. (2007) Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. Arthritis Res. Ther., 9 (5): R94. [PMID:17875202]

3. Barnea G, Strapps W, Herrada G, Berman Y, Ong J, Kloss B, Axel R, Lee KJ. (2008) The genetic design of signaling cascades to record receptor activation. Proc. Natl. Acad. Sci. U.S.A., 105 (1): 64-9. [PMID:18165312]

4. Biber K, Zuurman MW, Homan H, Boddeke HW. (2003) Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8. J. Leukoc. Biol., 74 (2): 243-51. [PMID:12885941]

5. Brouwer N, Zuurman MW, Wei T, Ransohoff RM, Boddeke HW, Biber K. (2004) Induction of glial L-CCR mRNA expression in spinal cord and brain in experimental autoimmune encephalomyelitis. Glia, 46 (1): 84-94. [PMID:14999816]

6. Clark VJ, Dean M. (2004) Characterisation of SNP haplotype structure in chemokine and chemokine receptor genes using CEPH pedigrees and statistical estimation. Hum. Genomics, 1 (3): 195-207. [PMID:15588479]

7. Clark VJ, Dean M. (2004) Haplotype structure and linkage disequilibrium in chemokine and chemokine receptor genes. Hum. Genomics, 1 (4): 255-73. [PMID:15588486]

8. Devitt E, Lawless MW, Sadlier D, A Browne J, Walsh C, Crowe J. (2010) Early viral and peripheral blood mononuclear cell responses to pegylated interferon and ribavirin treatment: the first 24 h. Eur J Gastroenterol Hepatol, 22 (10): 1211-20. [PMID:20631625]

9. Ernst MC, Issa M, Goralski KB, Sinal CJ. (2010) Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes. Endocrinology, 151 (5): 1998-2007. [PMID:20228173]

10. Fan P, Kyaw H, Su K, Zeng Z, Augustus M, Carter KC, Li Y. (1998) Cloning and characterization of a novel human chemokine receptor. Biochem. Biophys. Res. Commun., 243 (1): 264-8. [PMID:9473515]

11. Galligan CL, Matsuyama W, Matsukawa A, Mizuta H, Hodge DR, Howard OM, Yoshimura T. (2004) Up-regulated expression and activation of the orphan chemokine receptor, CCRL2, in rheumatoid arthritis. Arthritis Rheum., 50 (6): 1806-14. [PMID:15188357]

12. Hartmann TN, Leick M, Ewers S, Diefenbacher A, Schraufstatter I, Honczarenko M, Burger M. (2008) Human B cells express the orphan chemokine receptor CRAM-A/B in a maturation-stage-dependent and CCL5-modulated manner. Immunology, 125 (2): 252-62. [PMID:18397265]

13. Hyde CL, Macinnes A, Sanders FA, Thompson JF, Mazzarella RA, Faergeman O, van Wijk DF, Wood L, Lira M, Paciga SA. (2010) Genetic association of the CCR5 region with lipid levels in at-risk cardiovascular patients. Circ Cardiovasc Genet, 3 (2): 162-8. [PMID:20130232]

14. Kiss H, Darai E, Kiss C, Kost-Alimova M, Klein G, Dumanski JP, Imreh S. (2002) Comparative human/murine sequence analysis of the common eliminated region 1 from human 3p21.3. Mamm. Genome, 13 (11): 646-55. [PMID:12461651]

15. Leick M, Catusse J, Follo M, Nibbs RJ, Hartmann TN, Veelken H, Burger M. (2010) CCL19 is a specific ligand of the constitutively recycling atypical human chemokine receptor CRAM-B. Immunology, 129 (4): 536-46. [PMID:20002784]

16. Merfeld DM, Young LR, Tomko DL, Paige GD. (1991) Spatial orientation of VOR to combined vestibular stimuli in squirrel monkeys. Acta Otolaryngol Suppl, 481: 287-92. [PMID:1927397]

17. Monnier J, Lewén S, O'Hara E, Huang K, Tu H, Butcher EC, Zabel BA. (2012) Expression, regulation, and function of atypical chemerin receptor CCRL2 on endothelial cells. J. Immunol., 189 (2): 956-67. [PMID:22696441]

18. Muruganandan S, Roman AA, Sinal CJ. (2010) Role of chemerin/CMKLR1 signaling in adipogenesis and osteoblastogenesis of bone marrow stem cells. J. Bone Miner. Res., 25 (2): 222-34. [PMID:19929432]

19. Oostendorp J, Hylkema MN, Luinge M, Geerlings M, Meurs H, Timens W, Zaagsma J, Postma DS, Boddeke HW, Biber K. (2004) Localization and enhanced mRNA expression of the orphan chemokine receptor L-CCR in the lung in a murine model of ovalbumin-induced airway inflammation. J. Histochem. Cytochem., 52 (3): 401-10. [PMID:14966207]

20. Otero K, Vecchi A, Hirsch E, Kearley J, Vermi W, Del Prete A, Gonzalvo-Feo S, Garlanda C, Azzolino O, Salogni L, Lloyd CM, Facchetti F, Mantovani A, Sozzani S. (2010) Nonredundant role of CCRL2 in lung dendritic cell trafficking. Blood, 116 (16): 2942-9. [PMID:20606167]

21. Shimada T, Matsumoto M, Tatsumi Y, Kanamaru A, Akira S. (1998) A novel lipopolysaccharide inducible C-C chemokine receptor related gene in murine macrophages. FEBS Lett., 425 (3): 490-4. [PMID:9563519]

22. Troyer JL, Nelson GW, Lautenberger JA, Chinn L, McIntosh C, Johnson RC, Sezgin E, Kessing B, Malasky M, Hendrickson SL et al.. (2011) Genome-wide association study implicates PARD3B-based AIDS restriction. J. Infect. Dis., 203 (10): 1491-502. [PMID:21502085]

23. Yoshimura T, Oppenheim JJ. (2008) Chemerin reveals its chimeric nature. J. Exp. Med., 205 (10): 2187-90. [PMID:18809717]

24. Zabel BA, Allen SJ, Kulig P, Allen JA, Cichy J, Handel TM, Butcher EC. (2005) Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. J. Biol. Chem., 280 (41): 34661-6. [PMID:16096270]

25. Zabel BA, Nakae S, Zúñiga L, Kim JY, Ohyama T, Alt C, Pan J, Suto H, Soler D, Allen SJ, Handel TM, Song CH, Galli SJ, Butcher EC. (2008) Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J. Exp. Med., 205 (10): 2207-20. [PMID:18794339]

26. Zuurman MW, Heeroma J, Brouwer N, Boddeke HW, Biber K. (2003) LPS-induced expression of a novel chemokine receptor (L-CCR) in mouse glial cells in vitro and in vivo. Glia, 41 (4): 327-36. [PMID:12555200]

Contributors

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How to cite this page

Amy E. Monaghan.
Chemokine receptors: CCRL2. Last modified on 19/02/2018. Accessed on 18/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=78.