Alternative titles; symbols
HGNC Approved Gene Symbol: RARRES2
Cytogenetic location: 7q36.1 Genomic coordinates (GRCh38) : 7:150,338,329-150,341,629 (from NCBI)
Retinoids exert their biologic effects through 2 families of nuclear receptors, retinoic acid receptors (e.g., 180240) and retinoid X receptors (e.g., 180245), which belong to the superfamily of steroid/thyroid hormone nuclear receptors. Using a subtraction hybridization approach, Nagpal et al. (1997) identified a human cDNA sequence, designated TIG2 by them, whose expression was upregulated by treatment of skin raft cultures with the synthetic retinoid tazarotene. The retinoid-mediated upregulation in TIG2 expression was confirmed by Northern blot analysis. The 830-bp TIG2 cDNA encodes a putative protein of 164 amino acids. TIG2 was neither expressed nor induced by tazarotene in primary keratinocyte and fibroblast cultures. Thus, TIG2 is expressed and induced by tazarotene only when keratinocytes and fibroblasts form a tissue-like 3-dimensional structure. Nagpal et al. (1997) found that TIG2 was expressed at high levels in nonlesional psoriatic skin but at lower levels in the psoriatic lesion and that its expression was upregulated in psoriatic lesions after topical application of tazarotene.
By screening a cell line expressing CHEMR23 (CMKLR1; 602351), followed by reverse-phase HPLC and mass spectrophotometric analysis, Wittamer et al. (2003) identified the active product of TIG2, which they called chemerin, as the CHEMR23 ligand. The 137-amino acid chemerin protein is generated from the 164-amino acid preprochemerin by cleavage of the signal peptide and proteolytic cleavage of 6 C-terminal amino acids by an extracellular protease. Human chemerin shares 65% amino acid identity with its mouse homolog. RT-PCR detected abundant chemerin expression in liver, lung, pituitary, and ovary, with lower levels in most other tissues examined; no expression was detected in peripheral blood leukocytes.
Wittamer et al. (2003) found that chemerin induced calcium mobilization in and migration of macrophages and immature dendritic cells in a CHEMR23-dependent manner. Monoclonal antibodies to CHEMR23 blocked chemerin-induced calcium mobilization in CHEMR23-expressing cell lines. Ascitic fluids from ovary carcinoma patients and synovial fluids from rheumatoid arthritis patients showed significant levels of active chemerin, whereas synovial fluids from osteoarthritis patients did not, suggesting that chemerin is present in inflammatory pathologic situations. Wittamer et al. (2003) concluded that chemerin is a potent chemoattractant specific for antigen-presenting cells that requires proteolytic activation.
By screening cells overexpressing CHEMR23 with a hemofiltrate peptide library, followed by chromatographic purification, Meder et al. (2003) independently identified a 134-amino acid circulating form of TIG2 as the CHEMR23 ligand.
By generating a monoclonal antibody to CHEMR23 and screening circulating leukocytes by FACS analysis, Zabel et al. (2005) demonstrated expression of CHEMR23 on circulating plasmacytoid dendritic cells (DCs), but not on myeloid DCs or other blood cells. In vitro assays identified chemerin in serum, but not plasma, as a chemoattractant for CHEMR23-expressing cells. Zabel et al. (2005) concluded that CHEMR23 may be a key mediator of plasmacytoid DC recruitment from blood to tissue sites enriched in chemerin.
By flow cytometric analysis, Vermi et al. (2005) demonstrated CHEMR23 expression in 40% of myeloid DCs and virtually all plasmacytoid DCs. Transmigration of both DC populations across an endothelial cell layer was dependent on chemerin and CHEMR23. Immunohistochemical analysis of lymph nodes and tonsils showed CHEMR23 expression on DCs, but not on Langerhans cells. Chemerin was expressed on the luminal side of high endothelial venules. Chemerin was not expressed in normal skin, but it was expressed on endothelial cells lining dermal blood vessels of lupus erythematosus skin lesions in which plasmacytoid DCs were abundant. Vermi et al. (2005) proposed that CHEMR23-chemerin interaction has a key role in directing plasmacytoid DC traffic.
Zabel et al. (2008) identified chemerin as a protein that interacted with, but was not internalized by, mouse and human CCRL2 (608379). They proposed that CCRL2 focuses chemerin localization and thereby contributes to inflammatory processes mediated by CMKLR1.
Meder, W., Wendland, M., Busmann, A., Kutzleb, C., Spodsberg, N., John, H., Richter, R., Schleuder, D., Meyer, M., Forssmann, W. G. Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23. FEBS Lett. 555: 495-499, 2003. [PubMed: 14675762] [Full Text: https://doi.org/10.1016/s0014-5793(03)01312-7]
Nagpal, S., Patel, S., Jacobe, H., DiSepio, D., Ghosn, C., Malhotra, M., Teng, M., Duvic, M., Chandraratna, R. A. S. Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin. J. Invest. Derm. 109: 91-95, 1997. [PubMed: 9204961] [Full Text: https://doi.org/10.1111/1523-1747.ep12276660]
Vermi, W., Riboldi, E., Wittamer, V., Gentili, F., Luini, W., Marrelli, S., Vecchi, A., Franssen, J.-D., Communi, D., Massardi, L., Sironi, M., Mantovani, A., Parmentier, M., Facchetti, F., Sozzani, S. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin. J. Exp. Med. 201: 509-515, 2005. [PubMed: 15728234] [Full Text: https://doi.org/10.1084/jem.20041310]
Wittamer, V., Franssen, J.-D., Vulcano, M., Mirjolet, J.-F., Le Poul, E., Migeotte, I., Brezillon, S., Tyldesley, R., Blanpain, C., Detheux, M., Mantovani, A., Sozzani, S., Vassart, G., Parmentier, M., Communi, D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 198: 977-985, 2003. [PubMed: 14530373] [Full Text: https://doi.org/10.1084/jem.20030382]
Zabel, B. A., Nakae, S., Zuniga, L., Kim, J.-Y., Ohyama, T., Alt, C., Pan, J., Suto, H., Soler, D., Allen, S. J., Handel, T. M., Song, C. H., Galli, S. J., Butcher, E. C. Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J. Exp. Med. 205: 2207-2220, 2008. [PubMed: 18794339] [Full Text: https://doi.org/10.1084/jem.20080300]
Zabel, B. A., Silverio, A. M., Butcher, E. C. Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood. J. Immun. 174: 244-251, 2005. [PubMed: 15611246] [Full Text: https://doi.org/10.4049/jimmunol.174.1.244]