RARRES2 gene

The RARRES2 gene (RARRES2 stands for: Retinoic Acid Receptor Responder 2) is a protein-coding gene. The associated signaling pathways include the response to increased Ca2+ concentrations in the cytosol of platelets.

The RARRES2 gene encodes a secreted chemotactic protein, called chemerin, which initiates chemotaxis via the ChemR23-G protein-coupled ligand with seven transmembrane domains. The expression of this gene is upregulated by the synthetic retinoid tazarotene and is found in a variety of tissues. The active protein has several functions, including that of an adipokine and an antimicrobial protein with activity against bacteria and fungi.

The encoded protein chemerin is an adipocyte-secreted protein (adipokine) that regulates adipogenesis, metabolism and inflammation by activating the chemokine-like receptor 1 (CMKLR1). Also acts as a ligand for CMKLR2. Chemerin can also bind to C-C chemokine receptor-like 2 (CCRL2), but with a lower affinity than to CMKLR1 or CMKLR2 (De Henau O et al. 2016). Chemerin positively regulates adipocyte differentiation, modulates the expression of adipocyte genes involved in lipid and glucose metabolism, and may play a role in angiogenesis, a process essential for white adipose tissue expansion. Chemerin also acts as a proinflammatory adipokine, causing increased secretion of other proinflammatory and prodiabetic adipokines that further impair metabolic function of adipose tissue and have negative systemic effects, including impaired insulin sensitivity, altered glucose and lipid metabolism, and a decrease in vascular function in other tissues. May have both pro- and anti-inflammatory properties depending on the type of enzymatic cleavage by different classes of proteases. Chemerin acts as a chemotactic factor for leukocyte populations expressing CMKLR1, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Exerts an anti-inflammatory effect by preventing TNF/TNFA-induced VCAM1 expression and adhesion of monocytes in vascular endothelial cells. The effect is mediated by inhibition of NF-kappa-B and CRK/p38 activation through stimulation of AKT1/NOS3 signaling and nitric oxide production. Its dual role in inflammation and metabolism may provide a link between chronic inflammation and obesity as well as obesity-related diseases such as type 2 diabetes and cardiovascular disease. Furthermore, the encoded adipokine shows an antimicrobial function in the skin.

Chemerin and visfatin may act as new markers for inflammation in systemic scleroderma (Sawicka K et al. 2019). Patients with systemic scleroderma had higher chemerin levels than a control group (182.71 ± 33.94 ng/ml), with the difference being statistically significant. A positive correlation of chemerin and visfatin with the values of the inflammatory marker CRP has been demonstrated. In addition, chemerin shows a statistically significant positive correlation with the concentration of the complement component C3, while visfatin correlates with the C4 values (Pawlik KK et al.2020).

Diseases associated with RARRES2 include Mönckeberg's arteriosclerosis and psoriasis.

1. Albanesi C et al. (2009) Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J Exp Med 206:249-258.
2. Banas M et al. (2015) The expression and regulation of chemerin in the epidermis. PLoS One 10:e0117830.
3. De Henau O et al. (2016) Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2. PLoS One 11:e0164179.
4. Pawlik KK et al.(2020) BIOMARKERS OF DISEASE ACTIVITY IN SYSTEMIC SCLEROSIS. Wiad Lek 73:2300-2305.
5. Sawicka K et al. (2019) Visfatin and chemerin levels correspond with inflammation and might reflect the bridge between metabolism, inflammation and fibrosis in patients with systemic sclerosis. Postepy Dermatol Alergol 36:551-565.