ChemR23: An Orphan Adopted

With the increasing prevalence of chronic inflammatory diseases and cancer, there has been an effort to define in the mechanisms of antigen presenting cell (APC) recruitment. The chemokine-mediated lure of APCs, such as dendritic cells (DCs) and macrophages (Mfs), to inflammatory lesions represents an early event that would be an attractive potential target for clinical manipulation. However, the chemokine/chemokine receptor system is redundant and pleiotropic, and an APC-specific chemokine/chemokine receptor pair has been elusive (for reviews see 1,2).

Several years ago human ChemR23,3 also known as Dez in the mouse,4 was described as a seven-pass transmembrane, G protein-associated receptor related to the chemoattractant C3a and C5a complement receptors and the bacterial peptide fMLP receptor. Although only approximately 28% identical in amino acid (aa) sequence on average, ChemR23 is structurally very similar to the chemokine receptors and, like some of the chemokine receptors, ChemR23 has been implicated as a minor co-receptor for some strains of the human immunodeficiency virus.3 However, while none of the chemokine receptors are specific for APCs, ChemR23 expression appears to be restricted to DCs and Mfs.3,4 Since the discovery of this novel APC-specific, chemokine receptor-like molecule, it has been difficult to evaluate its potential as a therapeutic target as neither natural nor synthetic ligands have been described.5

Figure 1. The C-terminus of Prochemerin is cleaved extracellularly by an unknown
protease. Chemerin binds and activates its
antigen presenting cell (APC)-specific receptor, ChemR23, at low nanomolar levels. Receptor activation elicits release of intracellular Ca2+, prevention of cAMP accumulation, phosphorylation of MAP kinases, and ultimately pertussis toxin (PTX)-sensitive chemotaxis.

The same group that cloned the ChemR23 orphan receptor has recently discovered and characterized its ligand, Chemerin.5 The chemerin gene had been cloned previously as tig-2, a gene dysregulated in psoriatic skin, but otherwise poorly characterized with no specific function yet ascribed to the protein.6 The human chemerin/tig-2 gene encodes the 163 aa Prepro-chemerin, which contains an N-terminal, 16-aa signal peptide allowing Prochemerin to be secreted. Human Prochemerin is cleaved extracellularly by an unknown protease after residue 157, removing a C-terminal, 6-aa peptide to generate mature, active Chemerin. Mature, active human Chemerin is a 137 aa, 16 kDa protein that shares approximately 65% aa sequence identity with its mouse homolog.5 Aequorin (a luminescent G protein functional assay7), competitive binding, and GTPγ[35S] binding assays using purified natural Chemerin or recombinant bioactive C-terminal Chemerin peptide place Chemerin efficacy in the low nanomolar range. Chemerin binding to ChemR23 results in pertussis toxin (PTX)-sensitive release of intracellular Ca2+, prevention of cAMP accumulation, and phosphorylation of MAP kinases.5 Chemerin mRNA is expressed in liver, lung, pituitary, and ovary, but not in peripheral blood leukocytes. Chemerin protein is also expressed at low nanomolar levels in ovarian and liver cancer ascitic fluids as well as arthritic synovial fluids. Human recombinant Chemerin functions as a chemoattractant for Mfs and immature, but not mature, DCs. This effect was maximal again at low nanomolar concentrations and was PTX-sensitive. Further, an anti-ChemR23 monoclonal antibody was capable of neutralizing both Chemerin-dependent chemotaxis and Ca2+ flux.5

While it may be tempting to grant admission for Chemerin into the chemokine family based on functional definitions, important sequence, genomic and protein structure, and processing differences suggest closer relationships with the cathelicidins, cystatins, and others. Nevertheless, Chemerin, via ChemR23, does act as an inflammation-associated chemoattractant specific for Mfs and immature DCs.5 While further research is obviously needed, this system may represent an appealing target for the development of treatments aimed at manipulating early Mf and DC trafficking to inflammatory lesions.3,5


  1. Christopherson, K., II & R. Hromas (2001) Stem Cells 19:388.
  2. Luster, A. (2002) Curr. Opin. Immunol. 14:129.
  3. Samson, M. et al. (1998) Eur. J. Immunol. 28:1689.
  4. Methner, A. et al. (1997) Biochem. Biophys. Res. Commun. 233:336.
  5. Wittamer, V. et al. (2003) J. Exp. Med. 198:977.
  6. Nagpal, S. et al. (1997) J. Invest. Dermatol. 109:91.
  7. Dupriez, V.J. et al. (2002) Receptors Channels 8:319.