RESUMEN
Chemerin is a processed protein that acts on G protein-coupled receptors (GPCRs) for its chemotactic and adipokine activities. The biologically active chemerin (chemerin 21-157) results from proteolytic cleavage of prochemerin and uses its C-terminal peptide containing the sequence YFPGQFAFS for receptor activation. Here we report a high-resolution cryo-electron microscopy (cryo-EM) structure of human chemerin receptor 1 (CMKLR1) bound to the C-terminal nonapeptide of chemokine (C9) in complex with Gi proteins. C9 inserts its C terminus into the binding pocket and is stabilized through hydrophobic interactions involving its Y1, F2, F6, and F8, as well as polar interactions between G4, S9, and several amino acids lining the binding pocket of CMKLR1. Microsecond scale molecular dynamics simulations support a balanced force distribution across the whole ligand-receptor interface that enhances thermodynamic stability of the captured binding pose of C9. The C9 interaction with CMKLR1 is drastically different from chemokine recognition by chemokine receptors, which follow a two-site two-step model. In contrast, C9 takes an "S"-shaped pose in the binding pocket of CMKLR1 much like angiotensin II in the AT1 receptor. Our mutagenesis and functional analyses confirmed the cryo-EM structure and key residues in the binding pocket for these interactions. Our findings provide a structural basis for chemerin recognition by CMKLR1 for the established chemotactic and adipokine activities.
Asunto(s)
Adipoquinas , Quimiocinas , Receptores de Quimiocina , Humanos , Membrana Celular , Quimiocinas/metabolismo , Microscopía por Crioelectrón , Receptores de Quimiocina/metabolismoRESUMEN
Intestinal barrier immunity is essential for controlling gut microbiota without eliciting harmful immune responses, while its defect contributes to the breakdown of intestinal homeostasis and colitis development. Chemerin, which is abundantly expressed in barrier tissues, has been demonstrated to regulate tissue inflammation via CMKLR1, its functional receptor. Several studies have reported the association between increased expression of chemerin-CMKLR1 and disease severity and immunotherapy resistance in inflammatory bowel disease (IBD) patients. However, the pathophysiological role of endogenous chemerin-CMKLR1 signaling in intestinal homeostasis remains elusive. We herein demonstrated that deficiency of chemerin or intestinal epithelial cell (IEC)-specific CMKLR1 conferred high susceptibility to microbiota-driven neutrophilic colon inflammation and subsequent tumorigenesis in mice following epithelial injury. Unexpectedly, we found that lack of chemerin-CMKLR1 signaling specifically reduced expression of lactoperoxidase (LPO), a peroxidase that is predominantly expressed in colonic ECs and utilizes H2O2 to oxidize thiocyanates to the antibiotic compound, thereby leading to the outgrowth and mucosal invasion of gram-negative bacteria and dysregulated CXCL1/2-mediated neutrophilia. Importantly, decreased LPO expression was causally linked to aggravated microbiota-driven colitis and associated tumorigenesis, as LPO supplementation could completely rescue such phenotypes in mice deficient in epithelial chemerin-CMKLR1 signaling. Moreover, epithelial chemerin-CMKLR1 signaling is necessary for early host defense against bacterial infection in an LPO-dependent manner. Collectively, our study reveals that the chemerin-CMKLR1/LPO axis represents an unrecognized immune mechanism that potentiates epithelial antimicrobial defense and restricts harmful colonic neutrophilia and suggests that LPO supplementation may be beneficial for microbiota dysbiosis in IBD patients with a defective innate antimicrobial mechanism.
Asunto(s)
Carcinogénesis , Quimiocinas , Colitis , Colon , Microbioma Gastrointestinal , Péptidos y Proteínas de Señalización Intercelular , Lactoperoxidasa , Receptores de Quimiocina , Animales , Carcinogénesis/inmunología , Transformación Celular Neoplásica , Quimiocinas/genética , Quimiocinas/metabolismo , Colitis/inmunología , Colitis/microbiología , Colon/inmunología , Colon/microbiología , Peróxido de Hidrógeno/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Lactoperoxidasa/metabolismo , Ratones , Neutrófilos/inmunología , Receptores de Quimiocina/genética , Receptores de Quimiocina/metabolismoRESUMEN
The adipokine chemerin contributes to exercise-induced improvements in glucose and lipid metabolism; however, the underlying mechanism remains unclear. We aimed to confirm the impact of reduced chemerin expression on exercise-induced improvement in glycolipid metabolism in male diabetic (DM) mice through exogenous chemerin administration. Furthermore, the underlying mechanism of chemerin involved in changes in muscle mitochondria function mediated by androgen/androgen receptor (AR) was explored by generating adipose-specific and global chemerin knockout (adipo-chemerin-/- and chemerin-/-) mice. DM mice were categorized into the DM, exercised DM (EDM), and EDM + chemerin supplementation groups. Adipo-chemerin-/- and chemerin-/- mice were classified in the sedentary or exercised groups and fed either a normal or high-fat diet. Exercise mice underwent a 6-wk aerobic exercise regimen. The serum testosterone and chemerin levels, glycolipid metabolism indices, mitochondrial function, and protein levels involved in mitochondrial biogenesis and dynamics were measured. Notably, exogenous chemerin reversed exercise-induced improvements in glycolipid metabolism, AR protein levels, mitochondrial biogenesis, and mitochondrial fusion in DM mice. Moreover, adipose-specific chemerin knockout improved glycolipid metabolism, enhanced exercise-induced increases in testosterone and AR levels in exercised mice, and alleviated the detrimental effects of a high-fat diet on mitochondrial morphology, biogenesis, and dynamics. Finally, similar improvements in glucose metabolism (but not lipid metabolism), mitochondrial function, and mitochondrial dynamics were observed in chemerin-/- mice. In conclusion, decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, likely through changes in androgen/AR signaling.NEW & NOTEWORTHY Decreased chemerin levels affect exercise-induced improvements in glycolipid metabolism in male mice by increasing mitochondrial number and function, which is likely mediated by androgen/androgen receptor expression. This study is the first to report the regulatory mechanism of chemerin in muscle mitochondria.
Asunto(s)
Quimiocinas , Glucosa , Metabolismo de los Lípidos , Ratones Noqueados , Receptores Androgénicos , Animales , Quimiocinas/metabolismo , Masculino , Ratones , Metabolismo de los Lípidos/fisiología , Metabolismo de los Lípidos/genética , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Glucosa/metabolismo , Dieta Alta en Grasa , Diabetes Mellitus Experimental/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Condicionamiento Físico Animal/fisiología , Ratones Endogámicos C57BL , Mitocondrias Musculares/metabolismo , Mitocondrias/metabolismo , Andrógenos/metabolismo , Andrógenos/farmacología , Músculo Esquelético/metabolismoRESUMEN
Chemerin is an adipokine that contributes to metabolism regulation. Nucleus tractus solitarius (NTS) is the first relay station in the brain for accepting various visceral afferent activities for regulating cardiovascular activity. However, the roles of chemerin in the NTS in regulating sympathetic activity and blood pressure are almost unknown. This study aimed to determine the role and potential mechanism of chemerin in the NTS in modulating sympathetic outflow and blood pressure. Bilateral NTS microinjections were performed in anaesthetized adult male Sprague-Dawley rats. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were continuously recorded. Chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were highly expressed in caudal NTS (cNTS). Microinjection of chemerin-9 to the cNTS increased RSNA, MAP and HR, which were prevented by CMKLR1 antagonist α-NETA, superoxide scavenger tempol or N-acetyl cysteine, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodonium or apocynin. Chemerin-9 increased superoxide production and NADPH oxidase activity in the cNTS. The increased superoxide production induced by chemerin-9 was inhibited by α-NETA. The effects of cNTS microinjection of chemerin-9 on the RSNA, MAP and HR were attenuated by the pretreatment with paraventricular nucleus (PVN) microinjection of NMDA receptor antagonist MK-801 rather than AMPA/kainate receptor antagonist CNQX. These results indicate that chemerin-9 in the NTS increases sympathetic outflow, blood pressure and HR via CMKLR1-mediated NADPH oxidase activation and subsequent superoxide production in anaesthetized normotensive rats. Glutamatergic inputs in the PVN are needed for the chemerin-9-induced responses.
RESUMEN
Adipokines play essential roles in regulating a range of biological processes, but growing evidence indicates that they are also fundamental in immunological mechanisms and, primarily, inflammatory responses. Adipokines mediate their actions through specific receptors. However, although adipokine receptors are widely distributed in many cell and tissue types, limited data are available on their expression in mast cells (MCs) and, consequently, adipokine's significance in the modulation of MC activity within the tissues. In this study, we demonstrate that rat peritoneal MCs constitutively express the leptin receptor (i.e. LEPR), adiponectin receptors (i.e. ADIPOR1 and ADIPOR2) and the chemerin receptor (i.e. CMKLR1). We also found that LEPR, ADIPOR1, ADIPOR2 and CMKLR1 expression in MCs changes in response to stimulation by their specific ligands and some cytokines with potent proinflammatory properties. Furthermore, the involvement of intracellular signaling molecules in leptin-, adiponectin- and chemerin-induced MC response was analyzed. Overall, our findings suggest that adipokines leptin, adiponectin and chemerin can significantly affect the activity of MCs in various processes, especially during inflammation. These observations may contribute significantly to understanding the relationship between adipokines, immune mechanisms and diseases or conditions with an inflammatory component.
RESUMEN
Interactions between female metabolic status, immune response, and reproductive system functioning are complex and not fully understood. We hypothesized that chemerin, considered a hormonal link between the above-mentioned processes, influences endometrial functions, particularly cytokine secretion and signalling. Using porcine endometrial explants collected during early pregnancy and the estrous cycle, we investigated chemerin effects on the secretion of interleukins (IL-1ß, IL-6, IL-8), leukaemia inhibitory factor (LIF), tumour necrosis factor α (TNFα), transforming growth factor α (TGFα), and protein abundances of their respective receptors. Our results demonstrate chemerin modulation of cytokine secretion and receptor expression, with effects dependent on the stage of pregnancy and dose of chemerin. Furthermore, chemerin influences the phosphorylation of stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κß) in the endometrium. Chemerin multifaceted actions, such as involvement in immune response, cell proliferation, and tissue remodelling seem to be mediated by cytokines, at least in the endometrium. These findings underscore the potential crosstalk between chemerin and hormonal signalling pathways, providing insights into the complex mechanisms underlying early pregnancy establishment and maintenance.
RESUMEN
BACKGROUND: With aging, white adipose tissue (WAT) undergoes distribution change and browning inhibition, which could be attenuated by exercise. Adipokine chemerin exerts roles in the above changes of WAT, and our previous studies demonstrated the effect of decreased chemerin on exercise-induced improvement of glucose and lipid metabolism in high fat diet (HFD) feeding male mice, so this study is to clarify whether chemerin's effects on glucose and lipid metabolism are associated with the distribution and browning of WAT. METHODS: After diet and exercise interventions, body weight and adipose tissue contents in different depots of male mice were weighed, body composition and energy metabolism parameters were determined by Echo MRI Body Composition Analyzer and metabolic cage, respectively. The levels of serum adiponectin and leptin were detected by ELISA, and the protein levels of PGC-1α, UCP1, adiponectin and leptin in WAT were measured by Western blot. RESULTS: Chemerin knockout exacerbated HFD-induced weight gain, upregulated the increases of visceral and subcutaneous WAT (vWAT and sWAT, especial in sWAT), and inhibited WAT browning, but improved blood lipid. Exercise reduced the body weight and WAT distribution, increased sWAT browning and further improved blood lipid in aged HFD male mice, which were abrogated by chemerin knockout. Detrimental alterations of leptin, adiponectin and adiponectin/leptin ratio were discovered in the serum and WAT of aged HFD chemerin(-/-) mice; and exercise-induced beneficial changes in these adipokines were blocked by chemerin knockout. CONCLUSION: Chemerin influences blood lipid of aged male mice under HFD and exercise states through regulating the distribution and browning of WAT, which might be related to the changes of adiponectin, leptin and adiponectin/leptin ratio.
Asunto(s)
Adiponectina , Tejido Adiposo Pardo , Tejido Adiposo Blanco , Quimiocinas , Dieta Alta en Grasa , Leptina , Ratones Noqueados , Condicionamiento Físico Animal , Animales , Masculino , Tejido Adiposo Blanco/metabolismo , Condicionamiento Físico Animal/fisiología , Quimiocinas/metabolismo , Quimiocinas/sangre , Ratones , Leptina/sangre , Leptina/metabolismo , Adiponectina/metabolismo , Adiponectina/sangre , Tejido Adiposo Pardo/metabolismo , Envejecimiento/metabolismo , Envejecimiento/fisiología , Lípidos/sangre , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones Endogámicos C57BL , Metabolismo de los Lípidos/fisiología , Peso Corporal/fisiología , Metabolismo Energético/fisiología , Proteína Desacopladora 1/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismoRESUMEN
Recent studies already confirmed that placenta mitochondrial dysfunction is associated with the progression of gestational diabetes mellitus (GDM). Besides, a possible relationship between adipokine chemerin and disulfide-bond A oxidoreductase-like protein (DsbA-L) had been revealed, whereas the potential interaction remains unclear. In addition, very little is still known about the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway and its mechanisms of action in the context of GDM. The present study aims to investigate the underlying mechanism of cGAS-STING pathway and its regulatory relationship with chemerin in GDM. A total of 50 participants, including 25 cases of GDM patients and 25 pregnant women with normal glucose tolerance, were enrolled, and their placenta tissues at term labor were collected. Besides, an insulin resistance cell model was established on the human trophoblastic cell line to explore the molecular mechanism of chemerin on cGAS-STING pathway. Results showed that there were mitochondrial pathological changes in GDM placenta, accompanied by the decreased expression of DsbA-L, increased level of chemerin, and the activation of cGAS-STING pathway. In the insulin resistant cell model, overexpression of chemerin upregulated protein expression of DsbA-L, and recombinant chemerin presented time-dependent inhibition on the cGAS-STING pathway, but this effect was not dependent on DsbA-L. In conclusion, elevated chemerin is probably a protective mechanism, which may be a potential therapeutic strategy for GDM.
Asunto(s)
Diabetes Gestacional , Femenino , Humanos , Embarazo , Adipoquinas , Diabetes Gestacional/metabolismo , Nucleotidiltransferasas/metabolismo , Placenta/metabolismo , Transducción de SeñalRESUMEN
AIMS: Elevated levels of adipokine chemerin have been identified in oral squamous cell carcinoma (OSCC) and found to be associated with metastasis to the cervical lymph nodes. The underlying mechanism through which chemerin affects OSCC progression is unclear. The aims of this study were firstly to determine chemerin levels and cytokine concentrations in serum from patients with OSCC and in OSCC cell cultures, and secondly to observe chemerin effects on OSCC cell cytokine secretion, migration, and invasion in vitro. METHODS: Serum samples were collected from 20 patients diagnosed with OSCC, including groups with (LN+) and without (LN-) cervical lymph node metastasis. A Luminex liquid suspension assay was used to quantify serum concentrations of 27 types of cytokines. Correlations between chemerin and cytokines (i.e., IL-6, IL-15, GM-CSF, RANTES, TNF-α, and VEGF) were analyzed. ELISAs (enzyme-linked immunosorbent assays) were used to determine concentrations of chemerin and selected cytokines in serum and in supernatants of OSCC cell cultures (SCC9 and SCC25 cell lines). OSCC cells were stimulated with human recombinant chemerin, STAT3 inhibitor, or IL-6 together with TNF-α neutralizing antibodies. Phosphorylated STAT3 protein levels were measured with western blot analysis. OSCC cell migration and invasion were investigated with Transwell assays. RESULTS: Compared to the LN- group, OSCC patients with cervical lymph node metastasis had higher levels of IL-6 (P = 0.006), IL-15 (P = 0.020), GM-CSF (P = 0.036), RANTES (P = 0.032), TNF-α (P = 0.005), VEGF (P = 0.006), and chemerin (P = 0.001). Patients' serum chemerin levels correlated directly with IL-6, GM-CSF, TNF-α, and VEGF levels in OSCC patients. Exogenous recombinant chemerin treatment promoted secretion of IL-6 and TNF-α via activation of STAT3 in OSCC cells. Chemerin induced OSCC-cell migration and invasion, and these effects were reduced by IL-6 and TNF-α neutralizing antibodies. CONCLUSION: Our findings indicate that chemerin may play a role in advancing OSCC progression by increasing production of IL-6 and TNF-α, perhaps via a mechanism involving STAT3 signaling.
Asunto(s)
Carcinoma de Células Escamosas , Quimiocinas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Anticuerpos Neutralizantes , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Movimiento Celular , Citocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-15/metabolismo , Interleucina-15/farmacología , Interleucina-6/metabolismo , Metástasis Linfática , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello , Factor de Transcripción STAT3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Quimiocinas/metabolismoRESUMEN
The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28-effector CD8 T cells, CCR7- CD45RO+ effector memory, and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory T cells present gene, protein, and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4ß1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ T cells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ T cells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors in vivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 T cell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing T cells to the tumor microenvironment for immunotherapeutic purposes.
Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Animales , Ratones , Linfocitos T CD8-positivos/metabolismo , Receptores CCR7/metabolismo , Subgrupos de Linfocitos T/metabolismo , Células Asesinas Naturales/metabolismo , Neoplasias/metabolismo , Quimiocinas/genética , Quimiocinas/metabolismo , Microambiente Tumoral , Péptidos y Proteínas de Señalización Intercelular/metabolismoRESUMEN
AIM: Although macrovascular complications represent the leading cause of mortality in type 1 diabetes mellitus (T1DM), the prevalence of subtle macrovascular affection including peripheral artery disease (PAD) among children with T1DM and its genetic predictors remains to be unraveled. Increasing evidence suggests a link between adiponectin rs1501299 and chemerin rs17173608 gene polymorphism and atherogenesis, and insulin resistance. Hence, this study assess the prevalence of these variants among children with T1DM in comparison to healthy controls and their association with macrovascular complications, namely PAD and hyperlipidemia. METHODS: Fifty children with T1DM and 50 matched controls underwent a thorough assessment including adiponectin rs1501299 and chemerin rs17173608 gene polymorphisms, fasting lipids, glycated hemoglobin (HbA1c), and ankle-brachial index (ABI). Cochran-Armitage trend test was used to decide the risk allele and evaluate the association between the candidate variant and PAD using a case-control design. RESULTS: Children with T1DM were found to have significantly higher ABI (p = 0.011) than controls. Chemerin gene polymorphism was detected in 41 children with T1DM (82.0%), while adiponectin gene polymorphism was detected in 19 children (38.0%). Children with T1DM having GG chemerin variant and those having TT adiponectin variant had significantly higher cholesterol with significantly lower HDL-C and ABI than those having the other two variants (p < 0.005). Children with T1DM having abnormal ABI had significantly higher chemerin G (p = 0.017) and adiponectin T (p = 0.022) alleles than those with normal ABI. Cholesterol and ABI were independently associated with chemerin and adiponectin gene polymorphism by multivariable regression analysis. CONCLUSION: Children with T1DM having chemerin and adiponectin gene polymorphisms have significantly higher cholesterol and ABI than those without these polymorphisms and controls. TRIAL REGISTRATION: The Research Ethics Committee of Ain Shams University, approval number R 31/2021.
Asunto(s)
Diabetes Mellitus Tipo 1 , Enfermedad Arterial Periférica , Niño , Humanos , Adiponectina , Colesterol , Polimorfismo de Nucleótido SimpleRESUMEN
Chemerin and resistin are adipokines studied as potential markers for early diagnosis and disease severity in patients with knee osteoarthritis (KOA) Therefore, we aimed to investigate the associations serum and synovial levels of chemerin and resistin with inflammatory parameters and ultrasonographic scores (US) in KOA individuals. Serum was collected from 28 patients with KOA and synovial fluid was obtained from 16 of them. Another 31 age and sex matched cases with no joint disease were included as healthy controls. Concentrations of chemerin, resistin, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were determined with ELISA. Erythrocyte sedimentation rate (ESR), C-reactive protein, serum uric acid (UA) were measured in the patients group. Participants with KOA underwent US assessment using the Outcome Measures in Rheumatology (OMERACT) scores. Patients with KOA had statistically significant higher level of serum resistin than healthy controls [11.05 (3.78-24.13) ng/mL and 7.23 (3.83-12.19) respectively, p < 0.001]. A strong correlation was found between serum chemerin and ESR (r = 0.434, p = 0.021), uric acid (r = 0.573, p = 0.001) as well as the US (r=-0.872, p < 0.001). Serum resistin demonstrated significant association with TNF-alpha (r = 0.398, p = 0.044). In conclusion, both chemerin and resistin might contribute to inflammatory changes associated with KOA. Further studies are needed to elucidate their potential role in the pathogenesis of the disease.
RESUMEN
Visfatin, as a novel adipokine, is considered to play a role in periodontal inflammation. Chemerin is another newly identified adipokine that is possible to have a role in periodontitis firstly reported in our previous study. The aim of the current study is to evaluate the gingival crevicular fluid (GCF) levels of visfatin and chemerin in periodontitis and and compare these adipokine levels with before and after non-surgical periodontal treatment. Twenty-nine patients with Stage III Grade B periodontitis and eighteen healthy subjects included in this cross-sectional cohort study. Clinical periodontal parameters and GCF were obtained from all subjects. Eight weeks after the following non-surgical periodontal treatment including scaling and root planning, samples and clinical periodontal parameters were collected again in the periodontitis group. The levels of adipokines were analyzed with standard enzyme-linked immunosorbent assay. The levels of visfatin and chemerin were statistically significantly higher at periodontitis group as compared to healthy group (P < 0.001). Although, no changes were observed in visfatin levels after periodontal treatment (P > 0.05), chemerin levels were significantly decreased (P < 0.001). Also, no differences were observed as compared to the healthy group (P > 0.05). Visfatin and chemerin may play a role in the periodontal disease process. In addition, it can be considered that the decreased chemerin levels after non-surgical periodontal treatment may play an important role for developing host modulation strategies.
Asunto(s)
Periodontitis Crónica , Periodontitis , Humanos , Nicotinamida Fosforribosiltransferasa , Líquido del Surco Gingival , Estudios Transversales , Periodontitis/terapia , AdipoquinasRESUMEN
Adipose tissue is an active endocrine gland, synthesizing and secreting multiple signaling molecules termed adipokines. Following the detection of adipokines and their receptors in the mammary tissue of various species, it is indicated that adipokines play a role in the development of the mammary gland. The aim of the present study was to determine the concentration-dependent influence of three adipokines, leptin, adiponectin, and chemerin, on the viability, apoptosis, and secretory activity of BME-UV1 bovine mammary epithelial cells. The study confirmed that BME-UV1 cells contain the leptin receptor (Ob-R) protein, and express transcripts of adiponectin (ADIPOR1 and ADIPOR2) and chemerin (CMLKR1 and GPR1) receptors. Regardless of the administered dose, none of the three tested adipokines had an effect on the viability of BME-UV1 cells, and the number of apoptotic cells remained unchanged. However, chemerin (100 ng/mL) stimulated BME-UV1 cells to synthesize and secrete αS1-casein, the major protein component of milk. These results indicate that chemerin may be a potent regulator of the bovine mammary epithelial cells' functional differentiation, contributing, along with the major systemic hormones and local growth factors, to the development of the bovine mammary gland.
Asunto(s)
Apoptosis , Quimiocinas , Células Epiteliales , Glándulas Mamarias Animales , Animales , Bovinos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/citología , Quimiocinas/metabolismo , Femenino , Supervivencia Celular/efectos de los fármacos , Línea Celular , Receptores de Adiponectina/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Caseínas/metabolismo , Adiponectina/metabolismoRESUMEN
Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid ß (Aß). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aß plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aß deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1-/-). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aß plaques in APP/PS1-Cmklr1-/- mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aß42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aß42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aß plaques/Aß42.
Asunto(s)
Enfermedad de Alzheimer , Astrocitos , Quimiocinas , Péptidos y Proteínas de Señalización Intercelular , Placa Amiloide , Receptores de Quimiocina , Animales , Astrocitos/metabolismo , Quimiocinas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Receptores de Quimiocina/metabolismo , Receptores de Quimiocina/genética , Placa Amiloide/metabolismo , Placa Amiloide/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Humanos , Péptidos beta-Amiloides/metabolismo , Ratones Noqueados , Movimiento Celular , Transducción de Señal , Ratones Transgénicos , Ratones Endogámicos C57BLRESUMEN
This study aims to investigate the effects of Gualou Xiebai Banxia Decoction(GXBD) on type 2 diabetes mellitus(T2DM) combined with acute myocardial infarction(AMI) in rats via chemerin/chemokine-like receptor 1(CMKLR1)/peroxisome proliferator-activated receptor α(PPARα) signaling pathway, and to explore the mechanism of GXBD in alleviating glucose and lipid metabolism disorders. The SD rats were randomized into control, model, positive control, and low-and high-dose GXBD groups. The rat model of T2DM was established by administration with high-fat emulsion(HFE) by gavage and intraperitoneal injection with streptozotocin, and then coronary artery ligation was performed to induce AMI. The control and model groups were administrated with the equal volume of normal saline, and other groups were administrated with corresponding drugs by gavage. Changes in relevant metabolic indicators were assessed by ELISA and biochemical assays, and the protein levels of chemerin, CMKLR1, and PPARα in the liver, abdominal fat, and heart were determined by Western blot. The results showed that GXBD alleviated the myocardial damage and reduced the levels of blood lipids, myocardial enzymes, and inflammatory cytokines, while it did not lead to significant changes in blood glucose. Compared with the model group, GXBD down-regulated the expression of chemerin in peripheral blood and up-regulated the expression of cyclic adenosine monophosphate(cAMP) and protein kinase A(PKA) in the liver. After treatment with GXBD, the protein levels of chemerin and CMKLR1 in the liver, abdominal fat, and heart were down-regulated, while the protein levels of PPARα in the liver and abdominal fat were up-regulated. In conclusion, GXBD significantly ameliorated the disorders of glycolipid metabolism in the T2DM-AMI model by regulating the chemerin/CMKLR1/PPARα signaling pathway to exert a protective effect on the damaged myocardium. This study provides a theoretical basis for further clinical study of GXBD against T2DM-AMI and is a manifestation of TCM treatment of phlegm and turbidity causing obstruction at the protein level.
Asunto(s)
Diabetes Mellitus Tipo 2 , Medicamentos Herbarios Chinos , Infarto del Miocardio , Ratas , Animales , PPAR alfa/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ratas Sprague-Dawley , Transducción de Señal , Infarto del Miocardio/tratamiento farmacológico , QuimiocinasRESUMEN
The adipokine chemerin may support blood pressure, evidenced by a fall in mean arterial pressure after whole body antisense oligonucleotide (ASO)-mediated knockdown of chemerin protein in rat models of normal and elevated blood pressure. Although the liver is the greatest contributor of circulating chemerin, liver-specific ASOs that abolished hepatic-derived chemerin did not change blood pressure. Thus, other sites must produce the chemerin that supports blood pressure. We hypothesize that the vasculature is a source of chemerin independent of the liver that supports arterial tone. RNAScope, PCR, Western blot analyses, ASOs, isometric contractility, and radiotelemetry were used in the Dahl salt-sensitive (SS) rat (male and female) on a normal diet. Retinoic acid receptor responder 2 (Rarres2) mRNA was detected in the smooth muscle, adventitia, and perivascular adipose tissue of the thoracic aorta. Chemerin protein was detected immunohistochemically in the endothelium, smooth muscle cells, adventitia, and perivascular adipose tissue. Chemerin colocalized with the vascular smooth muscle marker α-actin and the adipocyte marker perilipin. Importantly, chemerin protein in the thoracic aorta was not reduced when liver-derived chemerin was abolished by a liver-specific ASO against chemerin. Chemerin protein was similarly absent in arteries from a newly created global chemerin knockout in Dahl SS rats. Inhibition of the receptor Chemerin1 by the receptor antagonist CCX832 resulted in the loss of vascular tone that supports potential contributions of chemerin by both perivascular adipose tissue and the media. These data suggest that vessel-derived chemerin may support vascular tone locally through constitutive activation of Chemerin1. This posits chemerin as a potential therapeutic target in blood pressure regulation.NEW & NOTEWORTHY Vascular tunicas synthesizing chemerin is a new finding. Vascular chemerin is independent of hepatic-derived chemerin. Vasculature from both males and females have resident chemerin. Chemerin1 receptor activity supports vascular tone.
Asunto(s)
Vasos Sanguíneos , Quimiocinas , Animales , Ratas , Técnicas de Silenciamiento del Gen , Hígado/metabolismo , Aorta/metabolismo , Quimiocinas/análisis , Quimiocinas/metabolismo , Músculo Liso Vascular/metabolismo , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologíaRESUMEN
The adipokine chemerin is the endogenous ligand of the chemokine-like receptor 1 (CMKLR1), a member of the family of G protein-coupled receptors (GPCRs). This protein ligand plays an important role in obesity and inflammatory processes. Stable receptor-ligand interactions are highly relevant for its different physiological effects such as the migration of immune cells towards sites of inflammation. Here, we demonstrate that negative charges in the CMKLR1 N terminus are involved in the formation of strong contacts with a specific positively charged patch at the surface of full-length chemerin, which is absent in the short nonapeptide agonist chemerin-9, thus explaining its reduced affinity. Using receptor chimera of G protein-coupled receptor 1 (GPR1) and CMKLR1, we were able to identify the residues of this interaction and its relevance for stable full-length chemerin binding. This could help to develop more potent ligands for the treatment of inflammation-related diseases.
Asunto(s)
Inflamación , Receptores Acoplados a Proteínas G , Humanos , Ligandos , Receptores de Quimiocina , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Chemerin is a protein encoded by the Rarres2 gene that acts through endocrine or paracrine regulation. Chemerin can bind to its receptor, regulate insulin sensitivity and adipocyte differentiation, and thus affect glucose and lipid metabolism. There is growing evidence that it also plays an important role in diseases such as inflammation and cancer. Chemerin has been shown to play a role in the pathogenesis of inflammatory and metabolic diseases caused by leukocyte chemoattractants in a variety of organs, but its biological function remains controversial. In conclusion, the exciting findings collected over the past few years clearly indicate that targeting Chemerin signaling as a biological target will be a major research goal in the future. This article reviews the pathophysiological roles of Chemerin in various systems and diseases,and expect to provide a rationale for its role as a clinical therapeutic target.
Asunto(s)
Quimiocinas , Péptidos y Proteínas de Señalización Intercelular , Humanos , Quimiocinas/metabolismo , Transducción de Señal , Factores Quimiotácticos/metabolismo , Inflamación/metabolismoRESUMEN
BACKGROUND: Chemerin is a chemoattractant protein with adipokine and antimicrobial properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. Chemerin bioactivity largely depends on carboxyl-terminal proteolytic processing that generates chemerin isoforms with different chemotactic, regulatory, and antimicrobial potentials. While these mechanisms are relatively well known, the role of alternative splicing in generating isoform diversity remains obscure. METHODS AND RESULTS: Using rapid amplification of cDNA ends (RACE) PCR, we determined RARRES2 transcript variants present in mouse and human tissues and identified novel transcript variant 4 of mouse Rarres2 encoding mChem153K. Moreover, analyses of real-time quantitative PCR (RT-qPCR) and publicly-available next-generation RNA sequencing (RNA-seq) datasets showed that different alternatively spliced variants of mouse Rarres2 are present in mouse tissues and their expression patterns were unaffected by inflammatory and infectious stimuli except brown adipose tissue. However, only one transcript variant of human RARRES2 was present in liver and adipose tissue. CONCLUSION: Our findings indicate a limited role for alternative splicing in generating chemerin isoform diversity under all tested conditions.