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.

The secondary injury cascade after spinal cord injury:an analysis of local cytokine/chemokine regulation

After spinal cord injury,there is an extensive infiltration of immune cells,which exacerbates the injury and leads to further neural degeneration.Therefore,a major aim of current research involves targeting the immune response as a treatment for spinal cord injury.Although much research has been performed analyzing the complex inflammatory process following spinal cord injury,there remain major discrepancies within previous literature regarding the timeline of local cytokine regulation.The objectives of this study were to establish an overview of the timeline of cytokine regulation for 2 weeks after spinal cord injury,identify sexual dimorphisms in terms of cytokine levels,and determine local cytokines that significantly change based on the severity of spinal cord injury.Rats were inflicted with either a mild contusion,moderate contusion,severe contusion,or complete transection,7 mm of spinal cord centered on the injury was harvested at varying times post-injury,and tissue homogenates were analyzed with a Cytokine/Chemokine 27-Plex assay.Results demonstrated pro-inflammatory cytokines including tumor necrosis factorα,interleukin-1β,and interleukin-6 were all upregulated after spinal cord injury,but returned to uninjured levels within approximately 24 hours post-injury,while chemokines including monocyte chemoattractant protein-1 remained upregulated for days post-injury.In contrast,several anti-inflammatory cytokines and growth factors including interleukin-10 and vascular endothelial growth factor were downregulated by 7 days post-injury.After spinal cord injury,tissue inhibitor of metalloproteinase-1,which specifically affects astrocytes involved in glial scar development,increased more than all other cytokines tested,reaching 26.9-fold higher than uninjured rats.After a mild injury,11 cytokines demonstrated sexual dimorphisms;however,after a severe contusion only leptin levels were different between female and male rats.In conclusion,pro-inflammatory cytokines initiate the inflammatory process and return to baseline within hours post-injury,chemokines continue to recruit immune cells for days post-injury,while anti-inflammatory cytokines are downregulated by a week post-injury,and sexual dimorphisms observed after mild injury subsided with more severe injuries.Results from this work define critical chemokines that influence immune cell infiltration and important cytokines involved in glial scar development after spinal cord injury,which are essential for researchers developing treatments targeting secondary damage after spinal cord injury.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Macrophage migration inhibitory factor facilitates astrocytic production of the CCL2 chemokine following spinal cord injury

Spinal cord injury causes accumulation of a large number of leukocytes at the lesion site where they contribute to excessive inflammation.Overproduced chemokines are responsible for the migratory process of the leukocytes,but the regulatory mechanism underlying the production of chemokines from resident cells of the spinal cord has not been fully elucidated.We examined the protein levels of macrophage migration inhibitory factor and chemokine C-C motif chemokine ligand 2 in a spinal cord contusion model at different time points following spinal cord injury.The elevation of macrophage migration inhibitory factor at the lesion site coincided with the increase of chemokine C-C motif chemokine ligand 2 abundance in astrocytes.Stimulation of primary cultured astrocytes with different concentrations of macrophage migration inhibitory factor recombinant protein induced chemokine C-C motif chemokine ligand 2 production from the cells,and the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine attenuated the stimulatory effect.Further investigation into the underlying mechanism on macrophage migration inhibitory factor-mediated astrocytic production of chemokine C-C motif chemokine ligand 2 revealed that macrophage migration inhibitory factor activated intracellular JNK signaling through binding with CD74 receptor.Administration of the macrophage migration inhibitory factor inhibitor 4-iodo-6-phenylpyrimidine following spinal cord injury resulted in the reduction of chemokine C-C motif chemokine ligand 2-recruited microglia/macrophages at the lesion site and remarkably improved the hindlimb locomotor function of rats.Our results have provided insights into the functions of astrocyte-activated chemokines in the recruitment of leukocytes and may be beneficial to develop interventions targeting chemokine C-C motif chemokine ligand 2 for neuroinflammation after spinal cord injury.

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.

Neuronal chemokines:new insights into neuronal communication after injury

Classically,chemokines were described as small proteins driving leukocyte migration.Nonetheless,more and more studies are showing the great variety of cell functions and tissues in which they participate,including neural cells.During the last years,research has highlighted the importance of chemokines in the nervous system,governing a wide range of processes (MesquidaVeny et al.,2021).This is evidenced for example by the crucial role played by CXCL12 during cortical development,or the homeostatic role of neuronal CX3CL1,preventing microglial activation.We are now certain that many chemokines and their receptors are widely expressed in neurons,and growing evidence has shown them as fundamental players in direct neuronal communication,both during homeostasis and after insult.

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.

Blocking postsynaptic density-93 binding to C-X3-C motif chemokine ligand 1 promotes microglial phenotypic transformation during acute ischemic stroke

We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.

CXC chemokines and chemokine receptors in gastric cancer: From basic findings towards therapeutic targeting

Gastric cancer is the fourth most common cancer,and the second-highest cause of cancer-related deaths worldwide.Despite extensive research to identify novel diagnostic and therapeutic agents,patients with advanced gastric cancer suffer from a poor quality of life and poor prognosis,and treatment is dependent mainly on conventional cytotoxic chemotherapy.To improve the quality of life and survival of gastric cancer patients,a better understanding of the underlying molecular pathologies,and their application towards the development of novel targeted therapies,is urgently needed.Chemokines are a group of small proteins associated with cytoskeletal rearrangements,the directional migration of several cell types during development and physiology,and the host immune response via interactions with G-protein coupled receptors.There is also growing evidence to suggest that chemokines not only play a role in the immune system,but are also involved in the development and progression of tumors.In gastric cancer,CXC chemokines and chemokine receptors regulate the trafficking of cells in and out of the tumor microenvironment.CXC chemokines and their receptors can also directly influence tumorigenesis by modulating tumor transformation,survival,growth,invasion and metastasis,as well as indirectly by regulating angiogenesis,and tumor-leukocyte interactions.In this review,we will focus on the roles of CXC chemokines and their receptors in the development,progression,and metastasis of gastric tumors,and discuss their therapeutic potential for gastric cancer.

Expression of CXC chemokine IP-10 in patients with chronic hepatitis B

BACKGROUND: Chemokines have strong chemoattractant effects and are involved in a variety of immune and inflammatory reactions, such as attracting activated T lymphocytes, neutrophils, monocytes and natural killer cells via the pathway of G protein-coupled receptors to sites of inflammatory injury and contribute to wound repair. This investigation was designed to assess the levels of chemokine interferon-gamma inducible protein-10 (IP-10) and IP-10 mRNA, and the relationship between IP-10 mRNA and HBV-DNA and alanine aminotransferase (ALT) in patients with chronic hepatitis B. METHODS: The levels of IP-10 mRNA in peripheral blood mononuclear cells (PBMCs) were kinetically detected by real-time polymerase chain reaction (PCR). The rate of chemokine/GAPDH was regarded as the extreme level of chemokine. The level of IP-10 in serum was measured by enzyme linked immunosorbent assay (ELISA), and the expression of IP-10 in hepatic biopsy tissue was detected by streptavidin-peroxidase (SP) immunohistochemistry. RESULTS: The level of IP-10 mRNA in the PBMCs of patients was 0.7387 +/- 0.0768 (lg cDNA/lg GAPDH); it was significantly higher in patients with chronic hepatitis B than that in normal controls (P<0.001). The level of IP-10 in the serum of patients was 660.9 +/- 75.5 pg/ml. There was a significant difference between patients with chronic hepatitis B and normal controls (P<0.05). In patients with chronic hepatitis B, the level of IP-10 mRNA in PBMCs was correlated with the IP-10 plasma level (r=0.7312, P<0.001), and the IP-10 plasma level was fairly correlated with the levels of ALT and HBV-DNA plasma (r=0.7235, P<0.001; r=0.7371, P<0.001). IP-10 was found by immunohistochemical analysis to be selectively upregulated on sinusoidal endothelium. CONCLUSIONS: The expression of IP-10 mRNA in PBMCs, IP-10 plasma concentration and the expression of IP-10 in sinusoidal endothelium are all high in patients with chronic hepatitis B. Chemokine IP-10 may play an important role in trafficking inflammatory cells to the local focus in the liver and induce the development of the chronicity of hepatitis B.

CXC family of chemokines as prognostic or predictive biomarkers and possible drug targets in colorectal cancer

Colorectal cancer(CRC) is the third most common cancer in men and the second most common cancer in women,worldwide. In the early stages of the disease, biomarkers predicting early relapse would improve survival rates.In metastatic patients, the use of predictive biomarkers could potentially result in more personalized treatments and better outcomes. The CXC family of chemokines(CXCL1 to 17) are small(8 to 10 kDa) secreted proteins that attract neutrophils and lymphocytes. These chemokines signal through chemokine receptors(CXCR) 1 to 8.Several studies have reported that these chemokines and receptors have a role in either the promotion or inhibition of cancer, depending on their capacity to suppress or stimulate the action of the immune system, respectively.In general terms, activation of the CXCR1/CXCR2 pathway or the CXCR4/CXCR7 pathway is associated with tumor aggressiveness and poor prognosis; therefore,the specific inhibition of these receptors is a possible therapeutic strategy. On the other hand, the lesser known CXCR3 and CXCR5 axes are generally considered to be tumor suppressor signaling pathways, and their stimulation has been suggested as a way to fight cancer.These pathways have been studied in tumor tissues(using immunohistochemistry or measuring mRNA levels)or serum [using enzyme-linked immuno sorbent assay(ELISA) or multiplexing techniques], among other sample types. Common variants in genes encoding for the CXC chemokines have also been investigated as possible biomarkers of the disease. This review summarizes themost recent findings on the role of CXC chemokines and their receptors in CRC and discusses their possible value as prognostic or predictive biomarkers as well as the possibility of targeting them as a therapeutic strategy.

Chemokine expression in hepatocellular carcinoma versus colorectal liver metastases

AIM： To evaluate and compare the expression profiles of CXCL12 （SDF-1）, CCL19 （MIP-3β）, CCL20 （MIP-3a） and CCL21 （6Ckine, Exodus2） and their receptors on RNA and protein levels in hepatocellular carcinoma （HCC） versus colorectal liver metastases （CRLM） and to elucidate their impact on the carcinogenesis and progression of malignant liver diseases. METHODS： Chemokine expression was analyzed by RT-PCR and ELISA in 11 cases of HCC specimens and in 23 cases of CRLM and corresponding adjacent nontumorous liver tissues, respectively. Expressions of their receptors CXCR4, CCR6 and CCR7 were analyzed by RT- PCR and Western blot analysis in the same cases of HCC and CRLM. RESULTS： Significant up-regulation for CCL20/CCR6 was detected in both cancer types. Moreover, CCL20 demonstrated significant overexpression in CRLM in relation to the HCC tissues. Being significantly up-regulated only in CRLM, CXCR4 displayed an aberrant expression pattern with respect to the HCC tissues. CONCLUSION： Correlation of CXCR4 expression with CRLM suggests CXCR4 as a potential predictive factor for CRLM. High level expression of CCL20 and its receptor CCR6 in HCC and CRLM with marked up-regulation of CCL20 in CRLM in relation to HCC tissues indicates involvement of the CCL20/CCR6 ligand-receptor pair in the carcinogenesis and progression of hepatic malignancies.

Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition

AIM: To identify the mechanisms of chemokine ligand 20(CCL20)-induced hepatocellular carcinoma(HCC) metastasis and evaluate it as a prognostic marker. METHODS: Expression of CCL20 was evaluated by immunohistochemistry in HCC tissues from 62 patients who underwent curative resection. The relationship between CCL20 expression and clinicopathologic features was analyzed. Univariate and multivariate analyses were performed to evaluate its predictive value for recurrence and survival of HCC patients. The expression levels ofepithelial-mesenchymal transition(EMT)-and signaling pathway-related proteins were evaluated by Western blotting and immunocytochemistry. The effects of CCL20 on HCC cell proliferation and migration were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenoltetrazolium bromide(MTT) and Transwell assays. RESULTS: CCL20 immunoreactivity was detected in all 62 patient specimens. CCL20 expression was associated with preoperative alpha-fetoprotein level(P = 0.043), tumor size(P = 0.000), tumor number(P = 0.008), vascular invasion(P = 0.014), and tumor differentiation(P = 0.007). Patients with high CCL20 expression had poorer recurrence-free and overall survivals compared to those with low CCL20 expression(both P < 0.001). CCL20 induced EMT-like changes in HCC cells and increased their proliferation and migration ability(P < 0.05). Western blotting and immunofluorescence staining showed that CCL20 induced an EMT-like phenotype in HCC cells, and increased expression of phosphorylated AKT, β-catenin and vimentin, and decreased E-cadherin expression(P < 0.05). The correlation analysis revealed that high CCL20 expression in HCC tissue specimens was negatively correlated with E-cadherin expression(13.33%, 4/30), and positively correlated with vimentin(90.0%, 27/30), β-catenin(96.67%, 29/30) and p-AKT(76.67%, 23/30) expression.CONCLUSION: CCL20 expression is associated with HCC recurrence and patient survival and promotes HCC cell proliferation and migration by inducing EMT-like changes via PI3K/AKT and Wnt/β-catenin pathways.

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

Chemokines play complex roles in cerebral ischemia

Ischemic stroke(IS) is a disease caused by deficiency of blood and oxygen in focal or complete brain,followed by inflammation cascade and other pathological reactions,which finally lead to irreversible damage to the cerebrum.For the inflammation is a key progress at the initiation of ischemia and poststroke,and chemokines work as vital cytokines in inflammation,we focus the roles of chemokines in IS.Studies have shown cerebral ischemia is associated with marked induction of both CXC and CC chemokines which resulting in extensive leukocyte infiltration in the ischemic brain,and neutrophil infiltration may increase cerebral edema inducing injury in the ischemic area.In addition,chemokines also shows other functions such as promote neuroblast migration,hematogenous cell recruitment and functional brain repair.Thus,a similar chemokine ligand/chemokine receptor pair can mediate both beneficial and detrimental effects depending on the window of observation and pathophysiological conditions.This manuscript reviews the studies about chemokine-mediated effects in cerebral ischemia/reperfusion and discusses the potential significance of these interactions in injury and repair of ischemic tissues.We also refer drug development based on the chemokines and clinical applications using chemokines as diagnostic or prognostic biomarkers in ischemic stroke.

Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages

BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.

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.

Chemokines and their receptors play important roles in the development of hepatocellular carcinoma

The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma(HCC). The chemokines and their receptors in the microenvironment influence the development of HCCby several aspects including:inflammation,effects on immune cells,angiogenesis,and direct effects on HCC cells. Regarding these aspects,pre-clinical research by targeting the chemokine system has yielded promising data,and these findings bring us new clues in the chemokine-based therapies for HCC.

Chemokines and hepatocellular carcinoma

Chemokines play a paramount role in tumor progres-sion. In hepatocellular carcinoma (HCC) progression, chemokines and their receptors play an intricate role. Currently, chemokines and their receptors such as the CXCL12-CXCR4 axis, CX3CL1-CX3CR1 axis and the CCL20-CCR6 axis have received much research attention. Although a large number of studies show that these axes are strongly associated with HCC, the exact mechanism by which these axes promote the growth and progression of HCC remains unknown. In this paper, several chemokines and their receptor interactions in HCC progression, growth and metastasis and immune response to HCC are reviewed.

Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection

Chemokines produced in the liver during hepatitis C virus(HCV) infection induce migration of activated T cells from the periphery to infected parenchyma.The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell(Th1/Tc1) response.These chemokines consist of CCL3(macrophage inflammatory protein-1α;MIP-1α),CCL4(MIP-1β),CCL5(regulated on activation normal T cell expressed and secreted;RANTES),CXCL10(interferon-γ-inducible protein-10;IP-10),CXCL11(interferon-inducible T-cell α chemoattractant;I-TAC),and CXCL9(monokine induced by interferon γ;Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors.Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C.The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection.When the adaptive immune response fails in this task,non-specific T cells without the capacity to control the infection are also recruited to the liver,and these are ultimately responsible for the persistent hepatic damage.The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection,and to maintain liver viability during the chronic phase,by impairing non-specific T cell migration.Some chemokines and their receptors correlate with liver damage,and CXCL10(IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome.The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.