Trends in Endocrinology & Metabolism
ReviewChemerin: at the crossroads of inflammation and obesity
Section snippets
Discovery
The chemerin gene, also known as tazarotene-induced gene 2 (TIG2) or retinoic acid receptor responder 2 (RARRES2), was originally identified as a novel retinoid-responsive gene in psoriatic skin lesions [1]. The first evidence for the biological function for the chemerin protein came later, with a report identifying it as a secreted ligand of the orphan G protein-coupled receptor chemokine-like receptor (CMKLR)1 [2]. More recent studies have demonstrated that chemerin also serves as a ligand
Structure and processing
Chemerin is translated as a 163 amino acid pre-proprotein that is secreted as a 143 amino acid (18 kDa) proprotein following proteolytic cleavage of a signal peptide 2, 8 (Figure 1). This proprotein has low biological activity, and requires further extracellular C-terminal processing by plasmin, carboxypeptidases or serine proteases of the coagulation, fibrinolytic and inflammatory cascades 2, 4, 8, 9, 10. Interestingly, the extent of C-terminal cleavage depends on the location from which
Inflammation and obesity
The first recognized function of chemerin, acting through CMKLR1, was to promote chemotaxis of immature dendritic cells (DCs) and macrophages [2]. It is now known that CMKLR1 is expressed in a number of immune cells, including immature plasmacytoid DCs, myeloid DCs, macrophages and natural killer (NK) cells 4, 10, 20 and that serum chemerin levels correlate with levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and C reactive protein (CRP) 21, 22.
Metabolism and obesity
In addition to having an important energy storage function, white adipose tissue serves as an active endocrine organ that secretes a number of hormone-like compounds, collectively termed adipokines 42, 43, 44. Adipokines include proinflammatory cytokines and related proteins, complement and complement-related proteins, proteins of the fibrinolytic cascade, vasoactive proteins, and other biologically active peptides with hormone-like actions. Adipokines affect adiposity, adipocyte metabolism and
Glucose homeostasis
Obesity is an established risk factor for insulin resistance and T2DM, and alterations in adipokine secretion in obesity are believed to play a significant role in the development of these metabolic disorders 72, 73, 74, 75, 76, 77, 78. The elevated serum chemerin levels observed in humans and mice suggest that chemerin might also influence the dysregulation of glucose metabolism that often occurs with obesity. However, it is important to note that hyperinsulinemia, which is commonly found in
Concluding remarks
Experimental evidence supports a role for chemerin in various aspects of human physiology/pathophysiology including obesity, inflammation and insulin resistance. The majority of human data indicates that chemerin is elevated in obesity/diabetes, and that the source of elevated serum chemerin levels is adipose tissue (Figure 2). However, the precise role of chemerin in these disorders remains unclear, and several key research questions merit further investigation (Box 1). In particular, studies
Acknowledgements
Figure 1 is based upon an original figure devised and generously provided by Dr Kerry Goralski, Dalhousie University. Research in the Sinal Laboratory is funded by the Canadian Institutes of Health Research. M.E. is the recipient of a studentship award from the Nova Scotia Health Research Foundation.
References (79)
Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin
J. Invest. Dermatol.
(1997)Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism
J. Biol. Chem.
(2007)Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23
FEBS Lett.
(2003)Chemokine-like receptor 1 expression by macrophages in vivo: regulation by TGF-beta and TLR ligands
Exp. Hematol.
(2006)Chemoattractants, extracellular proteases, and the integrated host defense response
Exp. Hematol.
(2006)Chemerin activation by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades
J. Biol. Chem.
(2005)Regulation of chemerin bioactivity by plasma carboxypeptidase N, carboxypeptidase B (activated thrombin-activable fibrinolysis inhibitor), and platelets
J. Biol. Chem.
(2009)Quantification of angiotensin-converting-enzyme-mediated degradation of human chemerin 145-154 in plasma by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry
Anal. Biochem.
(2007)The C-terminal nonapeptide of mature chemerin activates the chemerin receptor with low nanomolar potency
J. Biol. Chem.
(2004)Identification of a stable chemerin analog with potent activity toward ChemR23
Peptides
(2009)
The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues
Blood
Potential role of chemerin in recruitment of plasmacytoid dendritic cells to diseased skin
Biochem. Biophys. Res. Commun.
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans
J. Lipid Res.
Adipose tissue as an endocrine organ
Trends Endocrinol. Metab.
Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis
Biochem. Biophys. Res. Commun.
RARRES2, encoding the novel adipokine chemerin, is a genetic determinant of disproportionate regional body fat distribution: a comparative magnetic resonance imaging study
Metabolism
Interleukin-1beta induces the novel adipokine chemerin in adipocytes in vitro
Regul. Pept.
Chemerin—a new adipokine that modulates adipogenesis via its own receptor
Biochem. Biophys. Res. Commun.
Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes
FEBS Lett.
Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids
J. Exp. Med.
Neutrophil-mediated maturation of chemerin: a link between innate and adaptive immunity
J. Immunol.
Chemokine-like receptor 1 expression and chemerin-directed chemotaxis distinguish plasmacytoid from myeloid dendritic cells in human blood
J. Immunol.
Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin
J. Exp. Med.
Chemerin is a novel adipokine associated with obesity and metabolic syndrome
Endocrinology
Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis
J. Exp. Med.
Role of neutrophil proteinase 3 and mast cell chymase in chemerin proteolytic regulation
J. Leukoc. Biol.
Synthetic chemerin-derived peptides suppress inflammation through ChemR23
J. Exp. Med.
Chemerin peptides promote phagocytosis in a ChemR23- and Syk-dependent manner
J. Immunol.
Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes
Clin. Endocrinol. (Oxf.)
Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis
Eur. J. Endocrinol.
Psoriasis: dysregulation of innate immunity
Br. J. Dermatol.
Skin innate immune system in psoriasis: friend or foe?
J. Clin. Invest
CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation
Eur. J. Immunol.
Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment
J. Exp. Med.
Immune functions and recruitment of plasmacytoid dendritic cells in psoriasis
Autoimmunity
NK cells at the interface between innate and adaptive immunity
Cell Death Differ.
Plasmacytoid dendritic cells in immunity
Nat. Immunol.
The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions
J. Immunol.
Chemokine-like receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease
J. Immunol.
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