Chemerin: A Novel Link between Inflammation and Atherosclerosis?

Corresponding author: Eun-Jung Rhee Department of Endocrinology and Metabolism, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyeong-dong, Jongno-gu, Seoul 110-746, Korea E-mail: [email protected] Many factors contribute to the development of atherosclerosis. Over the past few years, understanding of the importance of inflammation during all stages of atherosclerosis, including its initiation through the progression and the complication of thrombosis, has increased greatly. Under normal conditions, the vessel wall has its own machinery to maintain vascular homeostasis. However, the balance is broken when repetitive metabolic stimuli resulting from hypertension, insulin resistance or obesity strike the vessel wall. Most of these metabolic stimuli disturb homeostasis through the initiation of inflammation, that is the recruitment of inflammatory cells, the increased adhesion molecules, secretion of chemoattractant and proinflammatory cytokines from the endothelial cells and the migration and proliferation of smooth muscle cells from media [1]. Among the top contributors of inflammatory stimuli are adipokines secreted from adipose tissue, which is now considered not as a mere mass of fat tissue, but an active organ that acts as a reservoir for energy in the energy excess state and as an active supplier of energy when the body runs short of it. Adipokines have diverse autocrine, paracrine and endocrine actions and have been implicated in the pathogenesis of metabolic syndrome and cardiovascular disease. Chemerin, also known as tazarotene-induced gene 2 protein (TIG2) or retinoid acid receptor responder 2 (RARRES2), was a recently identified novel adipokine that has a role in adaptive and innate immunity [2]. Chemerin acts as a secreted ligand of the orphan G protein-coupled receptor chemokine-like receptor (CMKLR) 1, chemokine (C-C motif) receptor-like (CCRL) 2 and the G protein-coupled receptor (GPR) 1. Various cell types involved in innate and adaptive immunity express CMKLR1, and chemerin is known to function as a chemoattractant that promotes recruitment of immune cells to sites of injury [3,4]. Chemerin is translated as a pre-protein that is secreted as a proprotein following the proteolytic cleavage of a signal peptide [3,5]. This proprotein has low biological activity, and requires further C-terminal processing by plasmin, carboxypeptidases or serine protease of the coagulation, fibrinolytic and inflammatory cascades. This processing is suggested to be the key regulatory mechanism that affects the concentration of bioactive chemerin. Increased chemerin expression in adipocytes was demonstrated in mice fed a high fat diet [6]. Chemerin is known to be induced during adipocyte differentiation and increases insulin-stimulated glucose uptake in adipocytes [7]. A recent study suggested that overexpression of human chemerin in low-density lipoprotein receptor knockout (LDLRKO) mice induced insulin resistance in skeletal muscle and administration of chemerin exacerbated glucose intolerance, lowered insulin levels, and decreased tissue glucose uptake in obese/diabetic mice [8]. In addition, chemerin is shown to be expressed differentially according to different fat depots [9]. In human studies, chemerin levels correlated with metabolic factors reEditorial