Impairment in Postischemic Neovascularization in Mice Lacking the CXC Chemokine Receptor 3
Ludovic WaeckelZiad MallatStéphane PotteauxChristophe CombadièreMichel ClergueMicheline DuriezBao LuCraig GérardBarrett J. RollinsAlain TedguiBernard LévyJean‐Sébastien Silvestre
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Abstract:
Inflammatory cell infiltration is a feature of postischemic neovascularization. However, mechanisms leading to leukocyte attraction to the site of neovascularization are still undefined. We hypothesized that the CXC chemokine receptor 3 (CXCR3) may contribute to leukocyte accumulation and subsequently to blood vessel growth in the ischemic area. Ischemia induced by femoral artery ligature improved the number of CXCR3-expressing cells and the level of its ligand, CXCL10. Angiographic score, blood flow recovery measurement, and capillary density analysis showed a significant decrease of ischemic/nonischemic leg ratio in CXCR3-deficient mice when compared with controls ( P <0.05), at day 21 after ischemia. Interestingly, this impairment was as important as that observed in mice deficient for the well known CC-chemokine monocyte chemoattractant protein-1 (MCP-1). At day 7 of ischemic injury, the number of CD3-positive T cells and Mac-3–positive monocytes/macrophages was 38% and 45% lower, respectively, in the ischemic leg of CXCR3-deficient mice compared with the control group ( P <0.05), suggesting an important role for CXCR3 in leukocyte recruitment into the ischemic area. VEGF protein content, a classical proangiogenic factor, was also markedly reduced (80% reduction) in ischemic leg of CXCR3-deficient mice ( P <0.01). Injection of bone marrow–derived mononuclear cells (BM-MNCs) isolated from wild-type animals restored the neovascularization reaction in CXCR3-deficient mice whereas BM-MNCs from CXCR3-deficient mice was ineffective. In conclusion, CXCR3 plays a key role in neovascularization and provides novel information on the mechanisms leading to leukocyte infiltration in the vessel growth area.Keywords:
CXCR3
CXC chemokine receptors
CXCL9
CXCL1
CXC chemokine ligand 10( CXCL10),also known as interferon-inducible protein-10( IP-10),is a small chemokine belonging to the non-ELR-CXC chemokine family,which plays a pivotal role in leukocyte trafficking and cellular and tissue functions,such as endothelial and vascular smooth muscle cells. CXCL10 is able to regulate a cascade of inflammatory responses by binding to specific CXCR3 receptor,regarded as vital manifestations in cardiovascular diseases( CVD). The purpose of this review is to describe the functions of CXCL10 in different CVDs and discuss the possibility of utilizing CXCL10 as a potential biomarker in CVD study pattern.
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C-X-C motif chemokine receptor 3 (CXCR3) is a G protein-coupled receptor for three ligands which are C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 [1]. Previously we have reported that CXCL10 promotes pro-inflammatory cytokine expression, and forms positive feedback loop [2], [3]. In the present study, we described mRNA expression of CXCL9 and CXCL11 under CXCL10 stimuli in the presence or absence of CXCR3 antagonist, JN-2 in bone marrow-derived macrophages (BMMs) and CD4+ T cells. In addition, we examined pro-inflammatory cytokine expression under CXCL9 or CXCL11 stimuli in BMMs and CD4+ T cells.
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The role of chemokines in virus-induced acute hepatic failure is not well defined. In this study, we investigated the role of CXC chemokine receptor 3 (CXCR3) and its ligands chemokine Mig/CXCL9 (monokine induced by IFN-gamma) and IP-10/CXCL10 (interferon-gamma-inducible protein 10) in the recruitment of intrahepatic lymphocytes and subsequent acute hepatic failure. Balb/cJ mice (6 to 8 weeks, female) were intraperitoneally injected with 100 PFU murine hepatitis virus strain 3 (MHV-3). The proportions and numbers of T cells and NK cells in liver, spleen, and blood as well as the expression of CXCR3 on T cells and NK cells post MHV-3 infection was analyzed by flow cytometry. The hepatic mRNA level of the CXCR3-associated chemokines (CXCL9 and CXCL10) was detected by realtime PCR. A transwell migration assay was used to assess the chemotactic effect of MHV-3-infected hepatocytes and CXCL10 on the splenic lymphocytes. Following MHV-3 infection, the number of hepatic NK cells and T cells and the frequencies of hepatic NK cells and T cells expressing CXCR3 increased markedly; however, in the spleen and peripheral blood, they both decreased significantly. Moreover, the hepatic mRNAs levels of CXCL9 and CXCL10 were significantly elevated post infection. The transwell migration assay demonstrated that MHV-3-infected hepatocytes have the capacity to attract and recruit the splenic NK cells and T cells, and CXCL10 plays a key role in lymphocyte mobilization from the spleen. These results indicate that interactions involving CXCR3 and its ligands (CXCL9 and CXCL10), especially CXCL10 may play a key role in the recruitment of intrahepatic lymphocytes and subsequent necroinflammation and acute hepatic failure. Key words: Chemokine, interferon gamma-inducible protein 10 (CXCL10), hepatic failure, natural killer cell, T cell.
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Background: The development of effective tools for the large-scale analysis of gene expression has provided new insights into the involvement of gene networks and regular pathways in various disease processes. The chemokine receptor CXCR3 is a G protein-coupled receptor found predominantly on T cells that is activated by three ligands as follow: CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC), and play a key role in immune and inflammatory responses by promoting recruitment and activation of different subpopulations of leukocytes. Aim of the work: The study is a logical functional approach for the development of serum markers chemokines that bind to CXC chemokine receptor 3 to determine whether they play a role in the future of immune system to clear HCV, these chemokines: CXCL9, CXCL10 and CXCL11. Patients and methods: 131 male and female patients with chronic hepatitis C virus (CHCV) infection, their age ranges between 22 and 55 years, selected from the National Hepatology and Tropical Medicine Research Institute. The included patients were divided to two groups, the first group: 80 patients were investigated for the predictive values of CXCL9,10,11 and CXCR3 chemokines in peripheral blood mononuclear cells (PBMCs), the second group were fifty one patients analyzed for the expression of surface markers on CD8+T cells. Twenty healthy individuals were included to serve as controls for each group. All the patients and controls were subjected to the following: history, clinical examination, abdominal ultrasonography and collection of blood samples for routine laboratory investigation and serological assay. Results: Chemokine CXCL9, CXCL10, CXCL11 and their receptor CXCR3 expression levels are induced in PBMCs during CHCV infection, associated with increased the expression levels of CD8+T cells in CHCV patients. Conclusion: The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. Recommendations: The regulationof 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, the blocking of chemokines and chemokine receptor engagement is a therapeutic strategy that should be explored in the near future for non-responders to current anti-HCV therapy.
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CXC chemokine ligand-10 belongs to the family of non-ELR-CXC chemokine,which participates in many autoimmune diseases.It can not only recruit specific subtypes of leukocytes to inflammation sites,but also reduce the blood supply to tumors and inhibit the growth of tumor.Meanwhile,CXCL10 and its receptor CXCR3 are significantly increased in liver inflammation,thyroid follicular epithelial cells and infiltration of inflammatory cells.This article reviewed the structure,biological function and the relationship of CXC chemokine ligand-10 and its receptor with multiple diseases.
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2149 INTRODUCTION: Despite the presence of tumor Ag-specific T cells in the periphery of vaccinated patients, melanoma evades immune-mediated destruction. Optimizing T cell trafficking is essential to immunotherapy and may be facilitated by enhanced chemokine receptor interactions. CXCR3 ligands (CXCL9-11) are known as IFN-inducible chemokines, but the effects of IFN-α compared with IFN-γ on these three chemokines are not known.
METHODS: Peripheral blood from 8 normal donors was incubated at 37 oC for 48h with clinically appropriate doses of either IFN-α (1x105 IU/ml) or IFN-γ (3.9 x105 IU/ml) and supernatants were assayed for CXCR3 ligands and for their ability to induce migration of activated T cells. Transwell chambers with 8μm untreated membranes were used. Antigen-stimulated human T cells were placed in the upper chamber and supernatants from IFN-treated PBL were diluted to 10% and placed in the lower chamber. The assay was incubated at 37oC for 4h and the cells in each chamber were counted. Control migration assays were run in parallel with the same activated T cell and supernatants from untreated PBLs.
RESULTS: Both IFN-γ and IFN-α increased the production of CXCR3 ligands from PBL of normal donors (cumulative levels 614,147 and 909,223 pg/ml, respectively, vs. 4,321 for control). IFN-γ was dominant in increasing CXCL9 (MIG) in all 8 patients (mean 300,989 pg/ml vs. 404 pg/ml for IFN-γ and IFN-α, respectively). There was a balanced effect of IFN-γ and IFN-α on CXCL10 (IP-10, >500,000 pg/ml each) and IFN-α had a dominant effect on CXCL11 (I-TAC) in 7 out of 8 patients (87.5%; 32,636 for IFN-α vs. 21,329 pg/mL for IFN-γ). There were wide variations in migratory effects caused by IFN-induced supernatants from different normal donors (2.7%-62.5% of cells migrated). The percentage of cells that migrated under each treatment condition was calculated for each subject and the differences in these percentages were computed as alpha minus control and gamma minus control. The means of these values were averaged over all subjects and were 0.18 (-0.25, 0.61) and 0.10 (-0.06, 0.26) for the IFN-α and -γ differences, respectively. Interestingly, these variations were not explained by the measured levels of chemokines CXCL9-11.
CONCLUSIONS: Chemokines CXCL9, CXCL10, and CXCL11 are induced by type 1 interferons, but there is striking differential susceptibility to IFN for each chemokine. The chemokine-enriched supernatants of IFN-treated mononuclear cells induce migration of antigen-activated human T cells. Preliminary data suggest that some migration effects of IFN-induced supernatants cannot be explained fully by the known IFN-inducible chemokines, raising the question of whether other chemokine-chemokine receptor interactions are affected by type I IFNs in a way that alters T cell trafficking. Better characterization of these interactions may provide new tools to improve immune-mediated therapy of cancer.
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M. Müller, S. Carter, M. J. Hofer and I. L. Campbell (2010) Neuropathology and Applied Neurobiology36, 368–387The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity – a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-γ, interferon-inducible protein-10 and interferon-inducible T cell α-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-γ, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases.
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