CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke

Mirabelli-Badenier, Marisol; Braunersreuther, Vincent; Viviani, Giorgio Luciano; Dallegri, Franco; Quercioli, Alessandra; Veneselli, Edvige; Mach, François; Montecucco, Fabrizio

doi:10.1160/th10-10-0662

Cited by 125 publications

(46 citation statements)

References 135 publications

(180 reference statements)

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“…8,9 Chemokines and their cognate receptors regulate both physiological and pathological processes in the central nervous system, and it is currently postulated that chemokines play a generally deleterious role by contributing to brain injury after cerebral ischemia-reperfusion. 10 We have shown that expression of numerous chemokinerelated genes is upregulated in the mouse brain from 4 hours for ≥3 days after ischemia-reperfusion, 11 raising the possibility that certain key chemokines/chemokine receptors could represent targets for acute stroke therapy. For example, we 538 Stroke…”

mentioning

confidence: 98%

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

Lee

Chu

Kim

et al. 2015

Stroke

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Background and Purpose-Expression of numerous chemokine-related genes is increased in the brain after ischemicstroke. Here, we tested whether post-stroke administration of a chemokine-binding protein (CBP), derived from the parapoxvirus bovine papular stomatitis virus, might reduce infiltration of leukocytes into the brain and consequently limit infarct development. Methods-The binding spectrum of the CBP was evaluated in chemokine ELISAs, and binding affinity was determined using surface plasmon resonance. Focal stroke was induced in C57Bl/6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion for 23 or 47 hours. Mice were treated intravenously with either bovine serum albumin (10 μg) or CBP (10 μg) at the commencement of reperfusion. At 24 or 48 hours, we assessed plasma levels of the chemokines CCL2/MCP-1 and CXCL2/MIP-2, as well as neurological deficit, brain leukocyte infiltration, and infarct volume. Results-The CBP interacted with a broad spectrum of CC, CXC, and XC chemokines and bound CCL2/MCP-1 and CXCL2/MIP-2 with high affinity (pM range). Stroke markedly increased plasma levels of CCL2/MCP-1 and CXCL2/ MIP-2, as well as numbers of microglia and infiltrating leukocytes in the brain. Increases in plasma chemokines were blocked in mice treated with CBP, in which there was reduced neurological deficit, fewer brain-infiltrating leukocytes, and ≈50% smaller infarcts at 24 hours compared with bovine serum albumin-treated mice. However, CBP treatment was no longer protective at 48 hours. Conclusions-Post-stroke administration of CBP can reduce plasma chemokine levels in association with temporary attenuation of brain inflammation and infarct volume development.

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confidence: 98%

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

Lee

Chu

Kim

et al. 2015

Stroke

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“…Similar reductions in chemotaxis were also noted for monocytes, macrophages, and monocyte-derived dendritic cells toward their cognate ligands in the presence of MVC (0.1–10 μM) [12]. These intrinsic immunomodulatory effects associated with CCR5 antagonism are highly desirable for the treatment of inflammatory and autoimmune conditions including graft-versus-host disease [13], multiple sclerosis [14], and ischemic stroke [15]. However, CCR5 has also been heavily implicated in the development of CD8 + T cells [16–18] which play a critical role in the clearance of virus-infected cells and in the pathogenesis of HIV infection [19,20].…”

Section: Ccr5 Biology and Chemokine Receptor-based Hiv Tropismmentioning

confidence: 80%

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Kim

Giesler

Tahirovic

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

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“…There are not enough studies considering levels of CXCL9 in stroke; however, it is known to be involved in inflammatory disorders such as atherosclerosis and rheumatoid arthritis, and participation with other inflammatory factors is well studied [3,12,14,19,20]. Its beneficial role in muscle reconstruction along with other chemokines is also well known [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…They are also functionally described as "homeostatic" (meaning that they are secreted constitutively and involved in immune surveillance and mostly lymphocyte traffic) or "inflammatory" (meaning that they mediate pro-inflammatory signals and induce leukocyteoriented locomotion to the damaged or infected tissue). Chemokines have also been shown to influence the phenomena of angiogenesis and cellular differentiation [12].…”

Section: Introductionmentioning

confidence: 99%

Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke

Amin¹,

Vakilian²,

Mahmoodi³

et al. 2017

Eurasian J Med

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Objective: Inflammation plays a significant role in the development of ischemic stroke. CXC chemokines play pleiotropic roles in prolonged leukocyte locomotion, astrocyte migration/activation, and neural attachment/sprouting in response to focal stroke. In this study, we aimed to explore the changes in serum levels of three chemokines, C-X-C motif chemokine ligand 1 (CXCL1), C-X-C motif chemokine ligand 9 (CXCL9), and C-X-C motif chemokine ligand 10 (CXCL10), in ischemic stroke patients at the time of admission and before discharge from the hospital ward. Materials and Methods:In this study, we recruited 43 unrelated ischemic stroke patients using an easy convenience method or accidental sampling which is a type of non-probability sampling that involves the sample being drawn from that part of the population that is close to hand. We also enrolled 50 genetically unrelated healthy controls showing no history of neurologic, cardiovascular, or inflammatory diseases. Serum levels of the considered chemokines were measured by enzyme-linked immunosorbent assay (ELISA) in patients and healthy controls.Results: No significant difference was observed in ischemic stroke patients following hospitalization and prior discharging from the hospital; however, there was a significant difference in serum levels of CXCL9 and CXCL10 between patients and healthy controls. We also found that the level of the chemokine was not related to gender or medical therapy. It appears that CXCL9 and CXCL10 are more predisposing factors and play a direct role in stroke considering that they were higher in patients than in healthy controls. Conclusion:We believe that this study might be used as a basis for further studies on more effective medication regimens to prevent the onset and subsequent complications of stroke. However, these mediators are useful diagnostic and prognostic tools rather than therapeutic tools.Keywords: Chemokine, ischemia, stroke ÖZ Amaç: Enflamasyon iskemik inme gelişiminde önemli bir rol oynar. CXC kemokinlerinin fokal inmeye yanıt olarak gelişen nöral bağlanma/filizlenme, astrosit migrasyon/aktivasyon ve uzamış lökosit lokomosyonunda pleiotropic etkileri vardır. Bu çalışmada iskemik inmeli hastalarda, C-X-C motif kemokin ligand 10 (CXCL10), C-X-C motif kemokin ligand 1 (CXCL1) ve C-X-C motif kemokin ligand 9'u (CXCL9) içeren üç kemokinin serum düzeyindeki değişikliklerinin hastaneye kabul ve taburculuk sırasında araştırılması amaçlanmıştır.Gereç ve Yöntem: Bu çalışmada, kolay uygunluk yöntemi kullanılarak birbiriyle ilişkisi olmayan 43 iskemik inmeli hasta incelendi. Ayrıca herhangi bir nörolojik, kardiyovasküler veya inflamatuvar hastalık öyküsü olmayan, genetik olarak birbiriyle bağlantısız 50 sağlıklı denek de çalışmaya dahil edildi. Hastalarda ve sağlıklı kontrollerde kemokinlerin serum düzeyleri enzime bağlı bağışıklık deneyi (ALISA) ile ölçüldü.Bulgular: Mevcut çalışmada, iskemik inme geçirdiği için hastaneye yatırılan ve taburcu edilen hastalarda anlamlı bir farklılık izlenmedi. Ancak, hastalar ve sağlıklı...

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CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke

Cited by 125 publications

References 135 publications

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Circulatory Levels of C-X-C Motif Chemokine Ligands 1, 9, and 10 Are Elevated in Patients with Ischemic Stroke

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