Reduced expression of chemerin in visceral adipose tissue associates with hepatic steatosis in patients with obesity

Objective: This study aimed to evaluate whether circulating levels and/or visceral adipose tissue (VAT) expression of recently described adipokines associate with histopathological severity of nonalcoholic fatty liver disease (NAFLD), independent of obesity and insulin resistance. Methods: Serum levels of adiponectin, omentin, chemerin, monocyte chemoattractant protein-1, and secreted frizzled-related protein 4 were measured using enzyme-linked immunosorbent assay in 81 patients with obesity and NAFLD and 18 lean control subjects. Expression in VAT was measured using real-time PCR and histopathological grading was scored using the NAFLD activity score (NAS). Results: When NAFLD patients were subdivided into groups with simple steatosis, borderline nonalcoholic steatohepatitis (NASH), and NASH, adiponectin serum levels and omentin expression were lower in NASH versus simple steatosis patients. Serum adiponectin was generally lower with higher histopathological grading. Chemerin VAT expression was negatively associated with NAS (r = -0.331, P = 0.022) and steatosis score (r = -0.335, P = 0.020), independent of age, BMI, and HOMA-IR. In addition, adjusting for chemerin VAT expression in a multivariate model explained part of the association between NAS and HOMA-IR. Conclusions: These findings suggest that lower VAT expression of chemerin in patients with obesity may be involved in the pathophysiology of hepatic steatosis, potentially by modulating the link between insulin resistance and NAFLD

The Chemerin/ChemR23 System Does Not Affect the Pro-Inflammatory Response of Mouse and Human Macrophages Ex Vivo

Macrophages constitute a major component of innate immunity and play an essential role in defense mechanisms against external aggressions and in inflammatory responses. Chemerin, a chemoattractant protein, is generated in inflammatory conditions, and recruits cells expressing the G protein-coupled receptor ChemR23, including macrophages. Chemerin was initially expected to behave as a pro-inflammatory agent. However, recent data described more complex activities that are either pro- or anti-inflammatory, according to the disease model investigated. In the present study, peritoneal macrophages were generated from WT or ChemR23−/− mice, stimulated with lipopolyssaccharide in combination or not with IFN-γ and the production of pro- (TNF-α, IL-1β and IL-6) and anti-inflammatory (IL-10) cytokines was evaluated using qRT-PCR and ELISA. Human macrophages generated from peripheral blood monocytes were also tested in parallel. Peritoneal macrophages from WT mice, recruited by thioglycolate or polyacrylamide beads, functionally expressed ChemR23, as assessed by flow cytometry, binding and chemotaxis assays. However, chemerin had no effect on the strong upregulation of cytokine release by these cells upon stimulation by LPS or LPS/IFN-γ, whatever the concentration tested. Similar data were obtained with human macrophages. In conclusion, our results rule out the direct anti-inflammatory effect of chemerin on macrophages ex vivo, described previously in the literature, despite the expression of a functional ChemR23 receptor in these cells

Identification and characterization of an endogenous chemotactic ligand specific for FPRL2

Chemotaxis of dendritic cells (DCs) and monocytes is a key step in the initiation of an adequate immune response. Formyl peptide receptor (FPR) and FPR-like receptor (FPRL)1, two G protein–coupled receptors belonging to the FPR family, play an essential role in host defense mechanisms against bacterial infection and in the regulation of inflammatory reactions. FPRL2, the third member of this structural family of chemoattractant receptors, is characterized by its specific expression on monocytes and DCs. Here, we present the isolation from a spleen extract and the functional characterization of F2L, a novel chemoattractant peptide acting specifically through FPRL2. F2L is an acetylated amino-terminal peptide derived from the cleavage of the human heme-binding protein, an intracellular tetrapyrolle-binding protein. The peptide binds and activates FPRL2 in the low nanomolar range, which triggers intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of extracellular signal–regulated kinase 1/2 mitogen-activated protein kinases through the Gi class of heterotrimeric G proteins. When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis. Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2

Relationship between Chemerin Levels and Cardiometabolic Parameters and Degree of Coronary Stenosis in Korean Patients with Coronary Artery Disease

BackgroundChemerin is a novel adipokine that is associated with inflammation and adipogenesis. However, it remains unclear whether chemerin is involved in patients with cardiovascular disease. We investigated whether the serum chemerin levels of Korean patients with coronary artery disease correlated with specific cardiometabolic parameters.MethodsIn total, 131 patients, all of whom had coronary artery stenosis exceeding 50%, participated in this study. Their serum chemerin levels and cardiometabolic parameters were measured. The serum chemerin levels of two groups of patients were compared; those with one stenotic vessel (n=68) and those with multiple stenotic vessels, including left main coronary artery disease (n=63).ResultsSerum chemerin levels correlated positively with the degree of coronary artery stenosis and fasting glucose, triglyceride, total cholesterol, low density lipoprotein cholesterol, and high sensitive C-reactive protein levels. The group with multiple stenotic vessels, including left main disease, had higher chemerin levels than the group with one stenotic vessel (t=-2.129, P=0.035). Multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease (odds ratio, 1.018; confidence interval, 0.997 to 1.040; P=0.091).ConclusionSerum chemerin levels have a significant correlation with several cardiometabolic risk factors and the degree of coronary artery stenosis in Korean patients with coronary artery disease. However, multiple binary logistic regression showed chemerin was not an independent risk factor of multiple vessel disease. Additional investigations are necessary to fully elucidate the role of chemerin in cardiovascular disease

Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids

Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (APCs) that play key roles in both innate and adaptive immunity. ChemR23 is an orphan G protein–coupled receptor related to chemokine receptors, which is expressed specifically in these cell types. Here we present the characterization of chemerin, a novel chemoattractant protein, which acts through ChemR23 and is abundant in a diverse set of human inflammatory fluids. Chemerin is secreted as a precursor of low biological activity, which upon proteolytic cleavage of its COOH-terminal domain, is converted into a potent and highly specific agonist of ChemR23, the chemerin receptor. Activation of chemerin receptor results in intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of p42–p44 MAP kinases, through the Gi class of heterotrimeric G proteins. Chemerin is structurally and evolutionary related to the cathelicidin precursors (antibacterial peptides), cystatins (cysteine protease inhibitors), and kininogens. Chemerin was shown to promote calcium mobilization and chemotaxis of immature DCs and macrophages in a ChemR23-dependent manner. Therefore, chemerin appears as a potent chemoattractant protein of a novel class, which requires proteolytic activation and is specific for APCs

Chemerin and Adiponectin Contribute Reciprocally to Metabolic Syndrome

Obesity and metabolic syndrome (MetS) are considered chronic inflammatory states. Chemerin, a novel adipokine, may play an important role in linking MetS and inflammation. We investigated the association of chemerin with inflammatory markers and with characteristics of MetS in apparently healthy overweight and obese adults. We studied 92 adults; 59 men and 33 women whose average body mass index (BMI) was 28.15±5.08 kg/m2. Anthropometric parameters, insulin resistance indices, lipid profiles, and inflammatory markers including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), adiponectin, and chemerin were measured. Controlling for age, gender, and BMI, serum chemerin level was positively correlated with body fat and serum triglyceride, and negatively correlated with adiponectin and high density lipoprotein cholesterol (HDL- C), and was not correlated with altered hsCRP or PTX3 levels. Among the low, moderate and high chemerin groups, high chemerin individuals are more likely to have lower HDL-C. Conversely, individuals in the low adiponectin group are more likely to have lower HDL-C and show more MetS phenotypic traits than moderate and high adiponectin subjects. To determine the relationships of chemerin and adiponectin to MetS and its components, participants were stratified into four groups based on their chemerin and adiponectin levels (high chemerin/high adiponectin, high chemerin/low adiponectin, low chemerin/high adiponectin, or low chemerin/low adiponectin). Participants who were in the high chemerin/low adiponectin group more likely to have dyslipidemia and MetS (OR: 5.79, 95% CI:1.00–33.70) compared to the other three group. Our findings suggest that chemerin and adiponectin may reciprocally participate in the development of MetS

Chemerin regulates β-cell function in mice

Although various function of chemerin have been suggested, its physiological role remains to be elucidated. Here we show that chemerin-deficient mice are glucose intolerant irrespective of exhibiting reduced macrophage accumulation in adipose tissue. The glucose intolerance was mainly due to increased hepatic glucose production and impaired insulin secretion. Chemerin and its receptor ChemR23 were expressed in β-cell. Studies using isolated islets and perfused pancreas revealed impaired glucose-dependent insulin secretion (GSIS) in chemerin-deficient mice. Conversely, chemerin transgenic mice revealed enhanced GSIS and improved glucose tolerance. Expression of MafA, a pivotal transcriptional factor for β-cell function, was downregulated in chemerin-deficient islets and a chemerin-ablated β-cell line and rescue of MafA expression restored GSIS, indicating that chemerin regulates β-cell function via maintaining MafA expression. These results indicate that chemerin regulates β-cell function and plays an important role in glucose homeostasis in a tissue-dependent manner

ChemR23 Dampens Lung Inflammation and Enhances Anti-viral Immunity in a Mouse Model of Acute Viral Pneumonia

Viral diseases of the respiratory tract, which include influenza pandemic, children acute bronchiolitis, and viral pneumonia of the elderly, represent major health problems. Plasmacytoid dendritic cells play an important role in anti-viral immunity, and these cells were recently shown to express ChemR23, the receptor for the chemoattractant protein chemerin, which is expressed by epithelial cells in the lung. Our aim was to determine the role played by the chemerin/ChemR23 system in the physiopathology of viral pneumonia, using the pneumonia virus of mice (PVM) as a model. Wild-type and ChemR23 knock-out mice were infected by PVM and followed for functional and inflammatory parameters. ChemR23−/− mice displayed higher mortality/morbidity, alteration of lung function, delayed viral clearance and increased neutrophilic infiltration. We demonstrated in these mice a lower recruitment of plasmacytoid dendritic cells and a reduction in type I interferon production. The role of plasmacytoid dendritic cells was further addressed by performing depletion and adoptive transfer experiments as well as by the generation of chimeric mice, demonstrating two opposite effects of the chemerin/ChemR23 system. First, the ChemR23-dependent recruitment of plasmacytoid dendritic cells contributes to adaptive immune responses and viral clearance, but also enhances the inflammatory response. Second, increased morbidity/mortality in ChemR23−/− mice is not due to defective plasmacytoid dendritic cells recruitment, but rather to the loss of an anti-inflammatory pathway involving ChemR23 expressed by non-leukocytic cells. The chemerin/ChemR23 system plays important roles in the physiopathology of viral pneumonia, and might therefore be considered as a therapeutic target for anti-viral and anti-inflammatory therapies

Developmental and tissue-specific expression of NITRs

Novel immune-type receptors (NITRs) are encoded by large multi-gene families and share structural and signaling similarities to mammalian natural killer receptors (NKRs). NITRs have been identified in multiple bony fish species, including zebrafish, and may be restricted to this large taxonomic group. Thirty-nine NITR genes that can be classified into 14 families are encoded on zebrafish chromosomes 7 and 14. Herein, we demonstrate the expression of multiple NITR genes in the zebrafish ovary and during embryogenesis. All 14 families of zebrafish NITRs are expressed in hematopoietic kidney, spleen and intestine as are immunoglobulin and T cell antigen receptors. Furthermore, all 14 families of NITRs are shown to be expressed in the lymphocyte lineage, but not in the myeloid lineage, consistent with the hypothesis that NITRs function as NKRs. Sequence analyses of NITR amplicons identify known alleles and reveal additional alleles within the nitr1, nitr2, nitr3, and nitr5 families, reflecting the recent evolution of this gene family