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Chemerin Signaling Pathway

Figure 1. Chemerin signaling pathway.

Overview of chemerin

Adipose tissue is mainly distributed under the skin and around the organs, in which the proportion of subcutaneous fat is the largest, and the concentration of circulating adipokines is largely determined. Chemokines have been included in the adipokines family in recent years, and their receptors in the body are chemokine receptor 1, which is a proven class of antigen presenting cell chemokines. Studies have confirmed that chemerin and its receptors are mainly found in adipose tissue, antigen presenting cells and liver cells, which can regulate adipocyte differentiation, and serum chemerin concentration is associated with obesity and lipid metabolism disorders. Goralski et al found that mouse embryonic preadipocytes cultured in vitro can produce chemerin through autocrine or paracrine forms. On the one hand, they can activate downstream signaling pathways in cells, and regulate expression of glucose transporter-4, adiponectin, and leptin then affects glycolipid metabolism. On the other hand, chemotaxis of dendritic cells or macrophages promotes local inflammatory response. Knockdown of chemerin or receptor genes in mice blocks mouse embryonic preadipocyte differentiation and alters mature adipocytes metabolic function, reducing body fat reserves. Population studies have shown that there is a positive correlation between serum chemerin levels and many inflammatory factors, while chronic low-grade inflammatory responses in obesity and metabolic syndrome patients are strong stimulant. Catalán et al. compared the metabolic indicators of obese patients with normal body types and found that serum chemerin concentration and C-reactive protein, von Willebrand factor, plasminogen activator inhibitor1, tumor necrosis factor-α, mononuclear cell chemoattractant protein-1 levels were highly correlated (P < 0.001), but the association no longer existed after adjusting for body mass index. Many scholars have suggested that serum chemerin concentration in the fasting state can be used as a biomarker for the degree of insulin resistance in healthy men, which is conducive to the early diagnosis and intervention of metabolic syndrome, while weight loss can significantly reduce serum chemerin levels.

Chemerin family

The human chemerin-encoding gene is 3289 bp in length and is in chromosome 7q36.1, which consists of 4 exons and 3 introns. Chemerin was cloned in 1997 by Nagpal et al. in the treatment of psoriasis with the tretinoin-based drug, taurine, which upregulates gene expression. In 2003, Wittamer et al purified chemerin from the ascites of ovarian cancer patients and demonstrated that it is a natural ligand for the G protein-coupled receptor chemR23, which is chemotactic for chemR23-expressing macrophages and immature dendritic cells. In 2007, Bozaoglu et al. first identified chemerin as an adipocytokine by signal sequence capture technology. Its mRNA is highly expressed in adipose tissue, regulating adipocyte differentiation and is associated with the pathogenesis of metabolic syndrome. Chemerin expression is slightly different in different species of tissue. It is expressed in all tissues of P. obesus (an underwater sandy bio-tun tuna, an animal model of obesity and type 2 diabetes), with the highest expression in liver, kidney, and adipose tissue, and expression in visceral adipose tissue significantly increased than subcutaneous adipose tissue. Chemerin is mainly expressed in mature adipocytes in adipose tissue. Goralski et al found that mouse chemerin had the highest expression in white adipose tissue, liver and placenta, followed by ovary, and expression in other tissues was lower than 5% in liver. The expression of chemerin in adipocytes in white adipose tissue of epididymis is twice as large as interstitial blood vessels. It is speculated that white fat cells are the source and target of chemerin. Chemerin is widely expressed in various tissues of the human body and is expressed in adipose tissue, adrenal gland, liver, lung, pancreas, placenta, ovary, skin, etc. Chemerin releases with prochemerin as a precursor. Prochemerin has a molecular mass of 18 KD. It is composed of 163 amino acids and has low biological activity. After excision of the amino-terminal amino acid by an extracellular serine protease, it becomes a chemotactic chemerin of 16 KD. To study the active peptides of chemerin, in recent years, many peptides derived from the carboxy-terminal region of prochemerin were synthesized to observe its effect on chemR23. The shortest chemerin bioactive peptide was chemerin-9, chemerin149-157 (NH2 -YFPGQFAFS). -COOH), this 9-peptide has most of the activity of the full-length protein, activating chemR23. Excision of lysine (K) from the carboxy terminus of the 10 peptide NH2-YFPGQFAFSK-COOH increased the migration activity of chemR23-transfected cells by a factor of 16, and further cleavage resulted in inactivation of the complex, whereas prolongation of the 9-peptide end did not enhance its activity.

Chemerin signaling pathway

  1. Chemerin signaling pathway cascade
    Chemerin exerts a biological effect by binding to its receptor, and three G protein-coupled receptors that have been found to bind to chemerin have been identified so far. Among them, the most important receptor is ChemR23, a protein encoded by the human cmklr1 gene. The cmklr1 gene is expressed in plasmacytoid dendritic cells (PDC), macrophages, cardiac muscle cells, adipocytes, and vascular endothelial cells. When the receptor ChemR23 binds to chemerin, it induces intracellular Ca2+ release, extracellular signal-regulated kinase phosphorylation, and inhibits the accumulation of cAMP by binding to G-protein-coupled heterotrimers, thereby inducing activation of intracellular signaling molecules and participating in metabolic and inflammatory reactions. The other two receptors that bind to chemerin to exert biological effects are GRP1 and CCRL2, respectively. The grp1 gene is mainly expressed in the interstitial blood vessels of white adipose tissue, and the mechanism of its signaling pathway is still unclear. Studies have shown that GPR1 binds to chemerin to increase the effect of inhibitory protein supplementation, in addition to inducing very small amounts of signaling. In addition, studies have shown that the combination of the two may affect glucose homeostasis, while cclr2 gene is expressed in neutrophils, dendritic cells, T cells, and macrophages, but no biological effects have been found. Chemeirn's first discovered function was to promote chemotaxis of various immune cells to the inflammatory response site by binding to the ChemR23 receptor, including immature plasma dendritic cells (DCs), bone marrow DCs, macrophages, and natural killer cells (NK), etc., At the same time, cmklr1 gene is also expressed in DCs, macrophages, and vascular endothelial cells, and more ChemR23 is produced under the catalysis of inflammatory factors. A number of studies have demonstrated that chemerin/ChemR23 levels in a variety of chronic inflammatory diseases such as psoriasis, chronic hepatitis, chronic obstructive pulmonary disease, chronic periodontitis, inflammatory bowel disease and other patients' serum, body fluids and it is elevated in the injured tissues and positively correlated with inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL6), and tumor necrosis factor-α (TNF-α). In addition, when the inflammatory factors such as IL1β, TNF-α, IL6, and IL8 are increased in the serum of patients with inflammatory diseases, the expression of chemerin is also increased. Although most researches on chemerin focus on supporting the inflammatory effects of chemerin, there are still some studies suggesting that chemerin may also exert its anti-inflammatory effects through the chemerin/CMKLR1 signaling pathway. Adrych et al. pointed out that chemerin slows the progression of pancreatitis by stimulating macrophage infiltration, platelet-derived growth factor (PDGF) and transforming growth factor β1 (TGFβ1). A study by Cash et al. showed that chemerin and a chemerin-derived protein named chemerin15 protect mice from inflammatory stimuli by competitively inhibiting zymosan, a process that relies on activation of CMKLR1. In addition, the fatty acid-derived molecule resolvin E1, which is a ChemR23 ligand with chemerin, has also been proposed to participate in at least a portion of the anti-inflammatory effects after activation of the CMKLR1 receptor, whereas it is unknown that  whether chemerin and resolvin E1 competefor the same position of CMKLR1 in vascular endothelial cells and smooth muscle cells, as well as the specific anti-inflammatory mechanism of chemerin. Li Nan et al found that the serum chemerin concentration in patients with essential hypertension (PH) was significantly higher than that in healthy people, and its level and body mass index (BMI), CRP, fasting blood glucose (GLU), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and fasting plasma insulin (FINS) were positively correlated, suggesting that chemerin may participate in the development and progression of essential hypertension by affecting insulin resistance, lipid metabolism, and inflammatory response.
  2. Pathway regulation
    Chemerin activity is regulated by a variety of factors, and Zabel et al. found that coagulation factors XIIa, VIIa, and plasmin, as well as inflammation-related elastase and cathepsin G, activate prochemerin by digestion. Wittamer et al. also demonstrated that polymorphonuclear cell (PMN)-released tissue zymase G and amylase convert prochemerin into active chemerin, and mass spectrometry demonstrates that the digested products are different. Recent studies have found that plasma carboxypeptidase N and B and platelets can regulate the bioactivity of chemerin. Guillabert et al. confirmed that neutrophil-derived proteolytic enzyme 3 and mast cell-derived chymotrypsin produce specific chemerin isoforms, which are inactive.
  3. Relationship with diseases
    Metabolic syndrome (MS)
    A study in Japan found that in 3T3-L1 adipocytes, chemerin regulates insulin sensitivity by enhancing insulin signaling to increase glucose uptake and autocrine/paracrine. Sell and other studies found that the secretion of chemerin in obese patients was significantly higher than that in the control group, which was related to body mass index (BMI) and fat cell size. Further studies found that increased chemerin release is related to IR, which induces skeletal muscle cells to produce IR. Bozaoglu et al found that in the animal model P. obesus mesenteric adipose tissue, the expression level of chemerin in the T2DM group was significantly higher than that in the normal blood glucose group, and positively correlated with body mass, fasting blood glucose and fasting plasma insulin. This proves that the chemerin in the circulation concentrations are associated with major phenotypes of MS such as BMI, blood triglycerides, and blood pressure, which may play a role in the pathophysiological changes in MS.
    Inflammation
    The anti-inflammatory effect of chemerin is mediated by chemR23. Early inflammation of polymorphonuclear leukocytes (PMNs) in inflamed tissues precedes APC. Studies have confirmed that proteases released by PMNs activate chemerin precursors, suggesting that chemerin is produced early in inflammation and has a great effect on the occurrence and development of inflammation.

References

  1. Ferland D J, Watts S W. Chemerin: A Comprehensive Review Elucidating the Need for Cardiovascular Research. Pharmacological Research. 2015, 99:351-361.
  2. Xie Q, Deng Y, Huang C, et al. Chemerin-induced mitochondrial dysfunction in skeletal muscle. Journal of Cellular & Molecular Medicine. 2015, 19(5):986-95.
  3. Mariani F, Roncucci L. Chemerin/chemR23 axis in inflammation onset and resolution. Inflammation Research. 2015, 64(2):85-95.
  4. Bobbert T, Schwarz F, Fischerrosinsky A, et al. Chemerin and prediction of Diabetes mellitus type 2. Clinical Endocrinology. 2015, 82(6):838-43.
  5. Rodríguezpenas D, Feijóobandín S, Garcíarúa V, et al. The Adipokine Chemerin Induces Apoptosis in Cardiomyocytes. Cellular Physiology & Biochemistry International Journal of Experimental Cellular Physiology Biochemistry & Pharmacology. 2015, 37(1):176.

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