C-X-C chemokine receptor type 7 antibody enhances neural plasticity after ischemic stroke

Stromal cell-derived factor-1 and its receptor C-X-C chemokine receptor 4(CXCR4) have been shown to regulate neural regeneration after stroke.Howeve r,whether stromal cell-derived factor-1 receptor CXCR7,which is widely distributed in the develo ping and adult central nervous system,participates in neural regeneration remains poorly unde rstood.In this study,we established rat models of focal cerebral ischemia by injecting endothelin-1 into the cerebral co rtex and striatum.Starting on day 7 after injury,CXCR7-neutralizing antibody was injected into the lateral ventricle using a micro drug delivery system for 6 consecutive days.Our results showed that CXCR7-neutralizing antibody increased the total length and number of sprouting co rticospinal tra ct fibers in rats with cerebral ischemia,increased the expression of vesicular glutamate transporter 1 and growth-related protein 43,marke rs of the denervated spinal cord synapses,and promoted the differentiation and maturation of oligodendrocyte progenitor cells in the striatum.In addition,CXCR7 antibody increased the expression of CXCR4 in the striatum,increased the protein expression of RAS and ERK1/2 associated with the RAS/ERK signaling pathway,and im proved rat motor function.These findings suggest that CXCR7 improved neural functional recovery after ischemic stroke by promoting axonal regeneration,synaptogenesis,and myelin regeneration,which may be achieved by activation of CXCR4 and the RAS/ERK1/2 signaling pathway.

Chemokine Receptors CCR1, CCR3, CCR7 and Chemokines CX3CL1 and CCL5 are Significantly Up-Regulated and Very Reliable for Acute Rejection Diagnosis of Kidney Transplants

Background: The allo-immune response following organ transplantation constitutes one of the main determinants concerning both short- and long- term outcomes in renal graft recipients. Chemokines and their receptors play a diversified and important role, either homeostatic or inflammatory and direct different immune-competent cell types to the allograft. While deeply studied in the last two decades, controversy persists as a result of chemokines’ pleiotropic actions. We report our analysis of CCR1, CCR3, CCR7, CCL5 and CX3CL1 expression or synthesis by graft-infiltrating cells in human kidney transplants (KTx). At the same time, we tested their robustness in diagnosing acute rejection. Methods: Fine-needle aspiration biopsies (Fnab) were performed either on days 7 or 14 post-transplantation among stable KTx and on the day of acute rejection (AR) diagnosis. Fnab cytopreparations were studied by the enzymatic avidin-biotin complex staining for CCR1, CCR3, CCR7 and CX3CL1. From another subgroup of cases, Fnab samples were cultured for 48 hours and the supernatants were analysed for CCL5 by ELISA. Results: The group of AR cases showed a significantly up-regulated expression of CCR1, CCR3, CCR7 and CX3CL1 and a significantly higher synthesis of CCL5. The positive predictive values were respectively 92%, 97%, 85%, 76% and 78% and negative predictive values were by the same order, 100%, 73%, 100%, 98% and 83%. Conclusions: Our study permits us to advance that CCR1 and CCR3 play a significant and non-redundant role in acute rejection, and it is the first report of CCR3 association with rejection, probably related to CCL5. The presence inside the graft of significant up-regulation for CCR7 surmises that part of antigen presentation may be performed there without being restricted to secondary lymphoid sites. Our results with CX3CL1 confirm other reports.

chemokine/chemokine receptor pair CC L20/CC R6 in humancolorectal malignancy:An overview

Chemokines belong to a superfamily of small, cytokinelike proteins, which induce multiple physiological functions, particularly cytoskeletal rearrangement and compartment-specific migration through their interaction with G-protein-coupled receptors. Chemokines and their receptors have been widely acknowledged as essential and selective mediators in leukocyte migration in inflammatory response. It is now established that the chemokine/chemokine receptor system is also used by cancer cells to direct lymphatic and haematogenous spreading and additionally has an impact on the site of metastatic growth of different tumours. In recent years an increasing number of studies have drawn attention to CC-chemokine cysteine motif chemokine ligand 20(CCL20) and its physiological sole receptor CCR6 to play a role in the onset, development and metastatic spread of various gastrointestinal cancer entities. Among various cancer types CCR6 was also demonstrated to be significantly overexpressed in colorectal cancer(CRC) and stimulation by its physiological ligand CCL20 has been reported to promote CRC cell proliferation and migration in vitro. Further, the CCL20/CCR6 system apparently plays a role in the organ-selective liver metastasis of CRC. Here we review the literature on expression patterns of CCL20 and CCR6 and their physiological interactions as well as the currently presumed role of CCL20 and CCR6 in the formation of CRC and the development of liver metastasis, providing a potential basis for novel treatment strategies.

Chemokine receptor 4 gene silencing blocks neuroblastoma metastasis in vitro

This study investigated the effects of small interfering RNA （siRNA）-mediated silencing of chemokine receptor 4 （CXCR4） on the invasion capacity of human neuroblastoma cell line SH-SY5Y in vitro. Three siRNAs targeting CXCR4 were chemically synthesized and individually transfected into SH-SY5Y cells. Expression of CXCR4 mRNA and protein was signiifcantly sup-pressed in transfected cells by all three sequence-speciifc siRNAs compared with control groups. Furthermore, the invasion capacity of SH-SY5Y cells was signiifcantly decreased following trans-fection with CXCR4-speciifc siRNA compared with the control groups. These data demonstrate that down-regulation of CXCR4 can inhibit in vitro invasion of neuroblastoma.

Clinical and prognostic significance of CC chemokine receptor type 8 protein expression in gastrointestinal stromal tumors

BACKGROUND Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal neoplasms of the gastrointestinal tract.Surgical resection and tyrosine kinase inhibitors are defined as the main treatments but cannot cure patients with advanced GIST,which eventually develops into recurrence and acquired drug resistance.Therefore,it is necessary to identify prognostic biomarkers and new therapeutic targets for GISTs.CC chemokine receptor type 8(CCR8)protein participates in regulation of immune responses.Recent studies on CCR8 in nonsmall cell lung cancer and colorectal cancer showed that it was highly expressed in tumor-infiltrating regulatory T cells and correlated with a poor prognosis.AIM To detect CCR8 expression in GIST tissues and analyze its relationships with clinicopathological features and prognosis in patients with GISTs.METHODS Tissue samples were used for the tissue microarrays construction.The microarrays were then subjected to immunohistochemical analyses to detect CCR8 expression.Next,Kaplan–Meier analysis was utilized to calculate the survival rate of patients with complete follow-up data,and the potential prognostic value of CCR8 was evaluated by Cox regression analysis.Finally,a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes single-gene enrichment chart of CCR8 was constructed using the STRING database.RESULTS CCR8-positive signals were detected as brown or brown-yellow particles by immunohistochemistry located in the cytoplasm.Among 125 tissue samples,74 had CCR8 high expression and 51 had low or negative expression.Statistical analyses suggested CCR8 was significantly correlated with tumor size,mitotic index,AFIP-Miettinen risk classification and tumor location.Kaplan–Meier and multivariate analyses showed that patients with low or negative CCR8 expression,mitotic index<5/high-power fields(HPF)and tumor diameter<5 cm had a better prognosis.Based on the STRING database,CCR8 was significantly enriched in biological processes such as tumor immunity,T lymphocyte chemotaxis,migration and pathways like the nuclear factor-κB and tumor necrosis factor pathways as well as intestinal immune regulation networks.CONCLUSION CCR8 is a prognostic biomarker for malignant potential of GISTs,with high expression correlated with malignancy and poor prognosis.

C-C chemokine receptor type 2-overexpressing exosomes alleviated experimental post-stroke cognitive impairment by enhancing microglia/macrophage M2 polarization

BACKGROUND Human-derived mesenchymal stromal cells have been shown to improve cognitive function following experimental stroke.The activity of exosomes has been verified to be comparable to the therapeutic effects of mesenchymal stromal cells.However,the effects of exosomes derived from human umbilical cord mesenchymal stem cells(HUC-MSCs)(ExoCtrl)on post-stroke cognitive impairment(PSCI)have rarely been reported.Moreover,whether exosomes derived from C-C chemokine receptor type 2(CCR2)-overexpressing HUC-MSCs(ExoCCR2)can enhance the therapeutic effects on PSCI and the possible underlying mechanisms have not been studied.AIM To investigate the effects of ExoCtrl on PSCI and whether ExoCCR2 can enhance therapeutic effects on PSCI.METHODS Transmission electron microscopy,qNano®particles analyzer,and Western blotting were employed to determine the morphology and CCR2 expression of ExoCtrl or ExoCCR2.ELISA was used to study the binding capacity of exosomes to CC chemokine ligand 2(CCL2)in vivo.After the intravenous injection of ExoCtrl or ExoCCR2 into experimental rats,the effect of ExoCtrl and ExoCCR2 on PSCI was assessed by Morris water maze.Remyelination and oligodendrogenesis were analyzed by Western blotting and immunofluorescence microscopy.QRT-PCR and immunofluorescence microscopy were conducted to compare the microglia/macrophage polarization.The infiltration and activation of hematogenous macrophages were analyzed by Western blotting and transwell migration analysis.RESULTS CCR2-overexpressing HUC-MSCs loaded the CCR2 receptor into their exosomes.The morphology and diameter distribution between ExoCtrl and ExoCCR2 showed no significant difference.ExoCCR2 bound significantly to CCL2 but ExoCtrl showed little CCL2 binding.Although both ExoCCR2 and ExoCtrl showed beneficial effects on PSCI,oligodendrogenesis,remyelination,and microglia/macrophage polarization,ExoCCR2 exhibited a significantly superior beneficial effect.We also found that ExoCCR2 could suppress the CCL2-induced macrophage migration and activation in vivo and in vitro,compared with ExoCtrl treated group.CONCLUSION CCR2 over-expression enhanced the therapeutic effects of exosomes on the experimental PSCI by promoting M2 microglia/macrophage polarization,enhancing oligodendrogenesis and remyelination.These therapeutic effects are likely through suppressing the CCL2-induced hematogenous macrophage migration and activation.Key words:Cognitive impairment;Stroke;Exosomes;C-C chemokine receptor type 2;Microglia/macrophage polarization;Remyelination.

CX3 chemokine receptor 1 deficiency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus

Previous studies have shown that microglia impact the proliferation and differentiation of neu- rons during hippocampal neurogenesis via the fractalkine/CX3 chemokine receptor i （CX3CRI） signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deficiency （CX3CRl^GFP/GFe）. Furthermore, after experimental seizures were induced with kainic acid in these CX3CRl-deficient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental findings indicate that the functional maturation of newborn neu- rons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deficiency.

Expression of CC Chemokine Ligand 20 and CC Chemokine Receptor 6 mRNA in Patients with Psoriasis Vulgaris

Summary: In order to explore the possible role of CC chemokine ligand 20 (CCL20) and its receptor CC chemokine receptor 6 (CCR6) in the pathogenesis of psoriasis, the expression levels of mRNA of them in psoriatic lesions were investigated. The skin biopsies were collected from skin lesions in 35 cases of psoriasis vulgaris and 18 normal controls. RT-PCR was used to semi-quantitatively analyze the mRNA expression of CCL20 and CCR6 in the psoriatic lesions and the normal skin tissues. The results showed that the mRNA of CCL20 and CCR6 was present in every specimen. The expression levels of CCL20 mRNA in skin lesions were 1.1397±0.0521, which were greatly higher than those in normal controls (0.8681±0.0308) (P<0.001). The expression levels of CCR6 mRNA in skin lesions were 1.1103±0.0538, significantly higher than in the controls (0.9131±0.0433, P<0.001). These findings indicate that up-regulated expression of CCL20 and CCR6 mRNA might be related to the pathogenesis of psoriasis.

Chemokine receptor 8 expression may be linked to disease severity and elevated interleukin 6 secretion in acute pancreatitis

BACKGROUND Acute pancreatitis(AP)is an inflammatory disease,which presents with epigastric pain and is clinically diagnosed by amylase and lipase three times the upper limit of normal.The 2012 Atlanta classification stratifies the severity of AP as one of three risk categories namely,mild AP(MAP),moderately severe AP(MSAP),and severe AP(SAP).Challenges in stratifying AP upon diagnosis suggest that a better understanding of the underlying complex pathophysiology may be beneficial.AIM To identify the role of the chemokine receptor 8(CCR8),expressed by T-helper type-2 Lymphocytes and peritoneal macrophages,and its possible association to Interleukin(IL)-6 and AP stratification.METHODS This study was a prospective case-control study.A total of 40 patients were recruited from the Chris Hani Baragwanath Academic Hospital and the Charlotte Maxeke Johannesburg Academic Hospital.Bioassays were performed on 29 patients(14 MAP,11 MSAP,and 4 SAP)and 6 healthy controls as part of a preliminary study.A total of 12 mL of blood samples were collected at Day(D)1,3,5,and 7 post epigastric pain.Using multiplex immunoassay panels,real-time polymerase chain reaction(qRT-PCR)arrays,and multicolour flow cytometry analysis,immune response-related proteins,genes,and cells were profiled respectively.GraphPad Prism^(TM) software and fold change(FC)analysis was used to determine differences between the groups.P<0.05 was considered significant.RESULTS The concentration of IL-6 was significantly different at D3 post epigastric pain in both the MAP group and MSAP group with P=0.001 and P=0.013 respectively,in a multiplex assay.When a FC of 2 was applied to identify differentially expressed genes using RT2 Profiler,CCR8 was shown to increase steadily with disease severity from MAP(1.33),MSAP(38.28)to SAP(1172.45)median FC.Further verification studies using RT-PCR showed fold change increases of CCR8 in MSAP and SAP ranging from 1000 to 1000000 times when represented as Log10,compared to healthy control respectively at D3.The findings also showed differing lymphocyte and monocyte cell frequency between the groups.With monocyte population frequency as high as 70%in MSAP at D3.CONCLUSION The higher levels of CCR8 and IL-6 in the severe patients and immune cell differences compared to MAP and controls provide an avenue for exploring AP stratification to improve management.

Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression

Migration of dendritic cells (DCs) into tissues and secondary lymphoid organs plays a crucial role in the initiation of innate and adaptive immunity. In this article, we show that cyclosporin A (CsA) impairs the migration of DCs both in vitro and in vivo. Exposure of DCs to clinical concentrations of CsA neither induces apoptosis nor alters development but does impair cytokine secretion, chemokine receptor expression, and migration. In vitro, CsA impairs the migration of mouse bone marrow-derived DCs toward macrophage inflammatory protein-3beta (MIP-3beta) and induces them to retain responsiveness to MIP-1alpha after lipopolysaccharide (LPS)-stimulated DC maturation, while in vivo administration of CsA inhibits the migration of DCs out of skin and into the secondary lymphoid organs. CsA impairs chemokine receptor and cyclooxygenase-2 (COX-2) expression normally triggered in LPS-stimulated DCs; administration of exogenous prostaglandin E2 (PGE2) reverses the effects of CsA on chemokine receptor expression and DC migration. Inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathway signaling by CsA may be responsible for the CsA-mediated effects on the regulation of chemokine receptor and cyclooxygenase-2 (COX-2) expression. Impairment of DC migration due to inhibition of PGE2 production and regulation of chemokine receptor expression may contribute, in part, to CsA-mediated immunosuppression.

Functions and mechanisms of chemokine receptor 7 in tumors of the digestive system

Chemokine(C-X-C motif)receptor 7(CXCR7),recently termed ACKR3,belongs to the G protein-coupled cell surface receptor family,binds to stromal cellderived factor-1[SDF-1,or chemokine(C-X-C motif)ligand 12]or chemokine(CX-C motif)ligand 11,and is the most common chemokine receptor expressed in a variety of cancer cells.SDF-1 binds to its receptor chemokine(C-X-C motif)receptor 4(CXCR4)and regulates cell proliferation,survival,angiogenesis and migration.In recent years,another new receptor for SDF-1,CXCR7,has been discovered,and CXCR7 has also been found to be expressed in a variety of tumor cells and tumor-related vascular endothelial cells.Many studies have shown that CXCR7 can promote the growth and metastasis of a variety of malignant tumor cells.Unlike CXCR4,CXCR7 exhibits a slight modification in the DRYLAIV motif and does not induce intracellular Ca^2+release following ligand binding,which is essential for recruiting and activating G proteins.CXCR7 is generally thought to work in three ways:(1)Recruitingβ-arrestin 2;(2)Heterodimerizing with CXCR4;and(3)Acting as a“scavenger”of SDF-1,thus lowering the level of SDF-1 to weaken the activity of CXCR4.In the present review,the expression and role of CXCR7,as well as its prognosis in cancers of the digestive system,were investigated.

Expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4^＋ T cells in CBA/J×DBA/2 mouse model, selectively induced by IL-4 and IL-10, regulates the embryo resorption rate

Background Chemokines and their receptors have been a research focus in transplantation immunology. Chemokines and their receptors play a role in lymphocyte recruitment and differentiation process. This study aimed to observe whether IL-4 and IL-10 may regulate the expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4^＋ T cells in CBA/J×DBA/2 mouse model and to explore the role of CCR3, CCR5, CXCR3 in immune tolerance in pregnancy. Methods The mouse model of spontaneous abortion （CBA/J×DBA/2） and the normal pregnant mouse model （CBA/J×BALB/c） were used. CBA/J×DBA/2 mice were injected with IL-4 （CBA/J×DBA/2-IL-4）, IL-4 and IL-10 （CBA/J×DBA/2-IL-4＋IL-10）, or normal saline （CBA/J×DBA/2-NS） as a control. The expression of CCR3, CCR5 and CXCR3 on CD4^＋ T cells from mouse peripheral blood was measured by the double-labelled FCM method, and the embryo resorption rate was also examined. Results The embryo resorption rate in the CBA/J×DBA/2 group without any treatment was significantly higher than that in the CBA/J×BALB/c group （17.9% vs 3.7%, P 〈0.01）. The embryo resorption rate in the CBA/J×DBA/2 group immunized with IL-4 or IL-4 together with IL-10 was significantly decreased, compared with that in the control and NS groups respectively. CCR3 expression on CD4^＋ T cells in the CBA/J×DBA/2 group without any treatment was significantly lower than that in the CBA/J×BALB/c group （0.3738±0.3575 vs 1.2190±0.2772, P 〈0.01）; both CCR5 （3.0900±1.5603 vs 1.2390±0.6361, P〈0.01） and CXCR3 （2.4715±0.9074 vs 0.9200±0.5585, P 〈0.01） expressions on CD4^＋ T cells of the CBA/J×DBA/2 group without any treatment were significantly higher than those of the CBA/J×BALB/c group. Significant up-regulation of CCR3 and down-regulation of CXCR3 were found in the CBA/J×DBA/2 group treated with IL-4 （CCR3： 2.0360±0.6944, CXCR3： 1.3510±0.5263, P〈0.01） or IL-4 and IL-10 （CCR3： 1.8160±1.0947, CXCR3：1.0940±0.7168, P〈0.01）. Because of the CCR5, IL-4 and IL-10 （1.9400±0.8504 vs 3.0900±1.5603, P 〈0.05）, but IL-4 alone （2.5310±1.3595 vs 3.0900±1.5603, P 〉0.05） treatment significantly decreased the expression of CCR5 in CBA/J×DBA/2. Conclusions The abnormal expression of CCR3, CCR5 and CXCR3 on CD4^＋ T cells may play an important role in the pathogenesis of spontaneous abortion. The pregnancy immune tolerance may be induced through selective induction of CCR3, CCR5 and CXCR3 expressions by IL-4 together with IL-10.

Distinct Effect of CD40 and TNF-Signaling on the Chemokine/Chemokine Receptor Expression and Function of the Human Monocyte-Derived Dendritic Cells

A key and limiting step in the process of human monocyte-derived dendritic cells （mDCs） for clinical use is their in vitro maturation and in vivo migration. We previously observed that CD40 signal facilitated human mDC growth and maturation. To further explore this process, mDCs generated with GM-CSF and IL-4 were co-cultured with apoptotic tumor cells for 24 hours, followed by incubating with anti-CD40 monoclonal antibody or TNF-a for 48 hours to generate mature DCs. The chemokine/chemokine receptor expression and functions of mature DCs upon various stimuli were determined. The expression of costimulatory molecules on apoptotic tumor cell-loaded mature DCs co-cultured with either anti-CD40 antibody （anti-CD40-DCs） or TNF-a （TNF-DCs） were up-regulated compared to immature DCs, consistent with the abilities of these cytokine to drive DC maturation in vitro. The mRNA levels of chemokines such as stromal cell-derived factor-1a （SDF-1a）, EBV-induced molecule 1 ligand chemokine （ELC）, and IFN inducible protein-10 （IP-10） in anti-CD40 activated DCs were increased and the dendritic cell-specific chemokine 1 （DC-CK1） was moderately up-regulated as compared with other mature DCs. The corresponding chemokine receptors CXCR4 and CCR7 of anti-CD40-DCs were significantly expressed. The CXCR3 expression on activated T cells stimulated by anti-CD40-DCs was also increased. Moreover, the anti-CD40-DCs had a stronger ability to stimulate T cell proliferation than any other DCs. The NF-xB activity was much higher in anti-CD40-DCs than that of TNF-DCs. These results offer further evidence of the importance of the CD40 signal in developing efficient human DC vaccines for cancer immune therapy. Cellular ＆ Molecular Immunology.

Effect of CO2 pneumoperitoneum on the expression of the chemokine receptors CXCR4 and CCR7 in colorectal carcinoma cells in vitro

Background The ability of pneumoperitoneum in laparoscopic surgery to promote proliferation and metastasis of colorectal cancer has become a focus of research in the field of minimally invasive surgery. The aim of this research was to investigate the effect of CO~ pneumoperitoneum under different pressures and exposed times on the expression of chemokine receptors in colorectal carcinoma cells. Methods We constructed an in vitro pneumoperitoneum model. SW480 colon carcinoma cells were exposed to CO2 pneumoperitoneum under different pressures （6, 9, 12, and 15 mmHg） for 1, 2, and 4 hours. These cells were then cultivated under the same conditions as normal SW480 colon carcinoma cells without CO= pneumoperitoneum （control group）, treated at 37℃, and 5% CO2. The expression of the chemokine receptors CXC receptor 4 （CXCR4） and chemokine C receptor 7 （CCR7） was detected by immunocytochemistry and reverse transcriptase polymerase chain reaction after being cultivated for 0, 24, 48, and 72 hours. Results Immunocytochemistry showed that CXCR4 expression in SW480 cells was significantly decreased in the 6, 9, 12, and 15 mmHg CO2 pneumoperitoneum-treated groups for the same exposure times compared with controls （P 〈0.05）. CCR7 expression in SW480 cells was significantly decreased in the 12 and 15 mmHg CO2 pneumoperitoneum- treated groups compared with controls （P 〈0.05）. CXCR4 and CCR7 expression increased up to the level of the control group after 24 and 48 hours （P 〉0.05）. If the CO2 pneumoperitoneum pressure increased, CXCR4 and CCR7 expression decreased at all exposure times. If the CO2 pneumoperitoneum exposure time prolonged, there were no significant differences in CXCR4 and CCR7 expression under the same pressure. Under all exposure times, CXCR4 and CCR7 mRNA expression was significantly decreased in the 6, 9, 12, and 15 mmHg CO2 pneumoperitoneum-treated groups （P 〈0.05） compared with controls, and it increased up to the level of controls after being cultivated for 48 hours （P 〉0.05）. If the CO2 pneumoperitoneum pressure increased （with all exposure times） and exposure time prolonged （under the same pressure）, there were no significant differences in CXCR4 and CCR7 expression. Conclusions CXCR4 and CCR7 expression is temporarily affected after continuous CO2 pneumoperitoneum treatment. The high pressure of CO2 pneumoperitoneum plays an important role in suppressing the expression of these chemokine receptors. Different lengths of time of exposure to a CO2 pneumoperitoneum-like environment do not change CXCR4 and CCR7 expression.

Overexpression of amplified in breast cancer 1 (AIB1) gene promotes lung adenocarcinoma aggressiveness in vitro and in vivo by upregulating C-X-C motif chemokine receptor 4

Background:We previously found that overexpression of the gene known as amplified in breast cancer 1(AIB1)was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma.However,the role of AIB1 in that malignancy remains unknown.The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis.Methods:A series of in vivo and in vitro assays were performed to elucidate the function of AIB1,while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis.Rescue experiments and in vitro assays were performed to investigate whether the invasive-ness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4(CXCR4).Results:The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo,whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion.CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma.The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels,whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo.Furthermore,we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients(183 cases),and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis.Conclusions:These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease.

Apoptosis in human germinal centre B cells by means of CC chemokine receptor 3 expression induced by interleukin-2 and interleukin-4

Background CC chemokine receptor 3 (CCR3), expressed on some inflammatory cells, is a member of the chemokine receptor family. Its ligand is eotaxin/CCL11. In this research, we studied the expression and function of CCR3 induced by interleukin-2 (IL-2) and interleukin-4 (IL-4) on human germinal centre (GC) B cells.Methods Cells isolated from human tonsils were stimulated with IL-2 or/and IL-4 followed by bonding with eotaxin/CCL11. Flow cytometry was used to detect expression of CCR3 on GC B cells and apoptosis of GC B cells. Real time quantitative reverse transcription polymerase chain reaction and Northern blot assays were used to analyse the CCR3 mRNA expressed in the GC B cells. Chemotaxis and adhesion assays were used to determine the effect of eotaxin/CCL11 ligand bonded to CCR3 on GC B cells.Results There was no CCR3 expression on human freshly isolated GC B cells. The combination IL-2 and IL-4 could upregulate CCR3 mRNA and protein expression on GC B cells. Eotaxin could not induce GC B cell chemotaxis and adhesion but triggered apoptosis of GC B cells.Conclusion IL-2 and IL-4 together induced expression of CCR3 on GC B cells, and the receptor acted as a death receptor.

Genetic variation in the chemokine receptor 5 gene and course of HIV infection;review on genetics and immunological aspect

Chemokines are small protein molecules associated with various physiological events precisely in immune modulation via dhemokine receptors.The chemokine receptors are G-protein coupled receptors express mainly on the cell surface of immune cells.Retrovi-ruses,including HIV in the early stage of infection,primarily target chemokines receptors and get intemalized easily into immune cells;T cell and escape from immune surveillance.HIV glycoprotein selectively develops an affinity for the extracellular domain of chemokines recep-tors and allows the pathogen to intemalize via CCR-5.Now,CCR-5 remains a crucial signaling pathway that can be translated into the therapeutic target by changing the receptor protein environment.Many populations have a mutation in coding and promoter regions of CCR-5,tun-ing a resistance for HIV infection.Natively,there are several mechanisms where the human genome remains in the dynamic state by changing its composition and acquiring variations.Sin-gle nucleotide polymorphism is spontaneous phenomenon responsible for precise and point mutation at the genome.Several studies have demonstrated that European and African Amer-ican populations are enriched in significant CCR5 promoter SNP(CCR5432)in the coding and promoter region as well.Now,such SNP can be an early-stage biomarker in studying HIV and other similar infections.Here,in this study,we have elucidated the role of SNP(both the pro-moter and coding region)and the fate of HIV infections.We also empathized with the genetics of such SNPs,mostly frequency and its immunological impact.

Chemokines and their receptors:important mediators to be aware of in neuroregenerative approaches for spinal cord injury

Curative therapy for spinal cord injury （SCI） remains elusive, however identifying options for tailored treatment strategies is in full swing. Like in the brain there are distinct regions in the adult spinal cord that harbor neural progenitor cells （NPCs） （Horner et al., 2000）. This offers the possibility of recruiting these cells in reparative approaches to support endogenous spinal cord regenerative capacities. Hereby, one challenge among many others is to overcome the already re- strictive microenvironment of potential endogenous NPCs, which is considerably akered by ongoing secondary lesion cascades by the initial lesion. Research addressing this aspect identified a plethora of mediators that hinder or promote neuroregeneration where at inflammatory mediators are known to play an essential role.

Foodborne toxin Aflatoxin B_(1)induced glomerular podocyte inflammation through proteolysis of RelA,downregulation of miR-9 and CXCR4/TXNIP/NLRP3 pathway

Aflatoxin B_(1)(AFB_(1))is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB_(1)induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB_(1)-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB_(1)increased ubiquitindependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB_(1)-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB_(1)-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB_(1)’s nephrotoxicity,leading to an effective protection of food safety and public health.

Role of chemokines in the hepatocellular carcinoma microenvironment and their translational value in immunotherapy

The difficulty of early diagnosis,high tumor heterogeneity,and high recurrence and metastasis rates lead to an unsatisfactory treatment status for hepatocellular carcinoma(HCC).HCC is a typical inflammation-driven tumor.Chronic inflammation allows nascent tumors to escape immunosurveillance.Chemokines are small,soluble,secreted proteins that can regulate the activation and trafficking of immune cells during inflammation.Several studies have shown that various chemokines with overarching functions disrupt the immune microenvironment during the initiation and progression of HCC.The dysregulated chemokine network in HCC contributes to multiple malignant processes,including angiogenesis,tumor proliferation,migration,invasion,tumor low response,and resistance to immune therapy.Here,we summarize the current studies focusing on the role of chemokines and their receptors in the HCC immune microenvironment,highlighting potential translational therapeutic uses for modulating the chemokine system in HCC.