Abstract W P199: Deficiency of Glia Maturation Factor Abrogates Brain Injury and Inflammation in a Murine Model of Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Western Blots ◽  
Ischemic Brain ◽  
Maturation Factor

Background and purpose: Glia maturation factor (GMF), a brain specific protein, discovered and characterized in our laboratory, induces expression of proinflammatory cytokines/ chemokines in the central nervous system (CNS). Recently, it has been demonstrated that deficiency of GMF mitigates neuronal damage in tissue culture cell and animal models of neurodegeneration. Since, GMF expression in brain enhances inflammation; we tested the hypothesis that deficiency of GMF abrogates the inflammatory responses in experimental model of ischemic stroke. Methods: Transient focal cerebral ischemia was induced by 1 hour of occlusion of the right middle cerebral artery (MCAO) with a 7.0 monofilament in GMF-containing wild type (Wt) and GMF-deficient (GMF-KO) mice. Mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the infarct volume and estimation of inflammatory responses. Immunohistochemistry and western blots were used to analyze the expression and activation of glial cells, and levels of NF-κB in ischemic brain hemisphere. Results: We found that levels of GMF significantly increased in MCAO mice compared to saline treated control mice. Next we found that GMF-KO mice exhibited significantly decreased infarct volume, and reduced neurological deficits compared to Wt mice. The decrease in infarct volume and neurological deficits in GMF-KO mice were correlated with a less activation of glia cells, downregulation of NF-κB and suppression of proinflammatory cytokines/chemokine in the ischemic region. Conclusions: In conclusion, present study provides the first evidence that deficiency of GMF reduces brain injury and inflammation after ischemic stroke and suggests that the effective suppression of endogenous GMF-function will prove to be an effective and selective strategy to slow deleterious inflammatory processes in ischemic brain injury. Keywords: Glia maturation factor; Ischemic stroke; Inflammation; Nuclear factor-κB; Cytokines

EDA-Containing Fibronectin Aggravates Ischemic Brain Injury In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 330-330
Author(s):  
Anil Chauhan ◽  
Mohammad M Khan ◽  
Chintan Gandhi ◽  
Neelam Chauhan ◽  
Asgar Zaheer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Experimental Model ◽  
Vascular Injury ◽  
Laser Doppler Flowmetry ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Doppler Flowmetry ◽  
Ischemic Brain

Abstract Abstract 330 Background: Fibronectin (FN) is a dimeric glycoprotein that plays an important role in several cellular processes, such as embryogenesis, malignancy, hemostasis, wound healing and maintenance of tissue integrity. FN is a ligand for many members of the integrin family (e.g. αIIbβ3, α5β1, α4β1, α9β1, αvβ3 and αvβ5) and also binds to thrombosis-related proteins including heparin, collagen and fibrin. FN generates protein diversity as a consequence of alternative processing of a single primary transcript. Two forms of FN exist; soluble plasma FN (pFN), which lacks the alternatively-spliced Extra Domain A (EDA); and insoluble cellular FN (cFN), which contains EDA. FN containing EDA (EDA+FN) is normally absent in plasma of human and mouse but EDA+FN has been found in patients with vascular injury secondary to vasculitis, sepsis, acute major trauma or ischemic stroke. We tested the hypothesis that elevated levels of plasma EDA+FN increase brain injury in an experimental model of ischemic stroke in mice. Model and Method: We used two genetically modified mouse strains: EDA+/+ mice contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+FN, whereas EDA-/- mice contain an EDA-null allele of the EDA exon and express only FN lacking EDA. Control EDAwt/wt mice contain the wild-type FN allele. Transient focal cerebral ischemia was induced by 60 minutes of occlusion of the right middle cerebral artery with a 7.0 siliconized filament in male mice (8-10 weeks in age). Mice were anesthetized with 1–1.5% isoflurane mixed with medical air. Body temperature was maintained at 37°C ± 1.0 using a heating pad. Laser Doppler flowmetry was used to confirm induction of ischemia and reperfusion. At 23 hours after MCAO, mice were evaluated for neurological deficits as a functional outcome and were sacrificed for quantification of infarct volume. For morphometric measurement eight 1 mm coronal sections were stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride (TTC). Sections were digitalized and infarct areas were measured blindly using NIS elements. Result: In EDA+/+ mice the percentage of infarct volume (mean ± SEM: 37.25 ± 4.11, n= 12,) in the ipsilateral (ischemic) hemisphere was increased by approximately two-fold compared to EDA wt/wt mice (mean ± SEM: 22.33 ± 3.39, n=11; P< 0.05, ANOVA) or EDA-/- mice (mean ± SEM: 21.72 ± 2.94, n=9). Regional cerebral blood flow during ischemia was not different among groups as assessed by laser Doppler flowmetry. The percentage increase in infarct volume in the EDA+/+ mice correlated well with severe neurological deficits (motor-deficit assessed by a four-point neurological score scale) compared to EDA wt/wt or EDA-/- mice. Because both thrombosis and inflammation contributes to brain injury during ischemic stroke, we investigated the time to form an occlusive thrombus in ferric-chloride carotid artery injury model by intravital microscopy. EDA+/+ mice demonstrated significantly faster time to occlusion (mean ± SEM: 12.35 ± 1.51 n=12,) compared to EDAwt/wt (Mean ± SEM: 17.27 ± 1.72 min, n=13, P<0.05, ANOVA) or EDA-/- (Mean ± SEM: 15.61 ± 1.76, n=11) mice. Additionally, the inflammatory response in the ischemic region was increased by two fold in EDA+/+ mice compared to EDA wt/wt and EDA-/- mice as sensed by myeloperoxidase activity and immunohistochemical analysis of neutrophils. Conclusion: EDA-containing FN is pro-thrombotic and pro-inflammatory, and aggravates ischemic brain injury in an experimental model of stroke in mice. The presence of EDA+FN in plasma may be a risk factor for vascular injury secondary to ischemic stroke. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Hua Zhu ◽  
Zhihong Jian ◽  
Yi Zhong ◽  
Yingze Ye ◽  
Yonggang Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Tissue ◽  
Proinflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Immunofluorescence Staining ◽  
Western Blots ◽  
Stat3 Pathway ◽  
Stat3 Signaling

BackgroundInflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses via the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms.MethodsRux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice in vivo and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling.ResultsRux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1β, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model in vitro.ConclusionJAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.

Abstract TP269: Lncrna-u90926 Aggravates Ischemic Brain Injury via Promoting Neutrophils Infiltration After Experimental Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jian Chen ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Expression Level ◽  
Neurological Deficits ◽  
Neurological Injury ◽  
Experimental Stroke ◽  
Ischemic Brain Injury ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Severity Scores

Background: Long non-coding RNAs (LncRNAs) are expressed at high levels in the brain in a variety of neuropathologic conditions, including stroke. However, the potential role of LncRNAs in ischemic stroke-associated microglial biological function and neurological injury remains largely unknown. Methods: Oxygen-glucose deprivation and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as in vitro and in vivo ischemic stroke models. Microarray analysis was performed to explore the overall expression level changes of LncRNAs. Real-time polymerase chain reaction (RT-qPCR) was used to detect expression level of LncU90926 in brain, plasma and microglia. ShRNA-LncU90926 in lentivirus and microglia specific Adeno-associated virus (AAV) were used to knockdown LncU90926 in vitro and in vivo separately. Infarct volumes and neurological impairments were assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, Neurological Severity Scores (NSS), rotarod test and grip strength respectively. Immunofluorescence staining and flow cytometry were performed to detect the number of neutrophils recruited to brain. RT-qPCR was used to detect the level of chemokines (CXCL, CCL2) and inflammatory mediators associated with neutrophils (MPO, MMP3 and TIMP1). Results: (1). LncU90926 was markedly up-regulated in the infarcted brain and plasma after MCAO. Both MCAO and OGD treatment induced remarkable up-regulation of LncU90926 in microglia. (2). LncU90926 knockdown definitely attenuated brain infarct size and neurological deficits after ischemic stroke. (3). LncU90926 knockdown in microglia reduced the number of neutrophils recruited to brain, and CXCL1 and CCL2 were down-regulated in both MCAO and OGD models. LncU90926 knockdown also induced reduction of MPO, MMP3 and TIMP1 in the infarcted brain. Conclusions: LncU90926 was up-regulated in microglia after experimental stroke, and aggravates ischemic brain injury through facilitating neutrophils infiltration via up-regulating microglial chemokine.

scholarly journals Inhibition of Perforin-Mediated Neurotoxicity Attenuates Neurological Deficits After Ischemic Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Yuhualei Pan ◽  
Dan Tian ◽  
Huan Wang ◽  
Yushang Zhao ◽  
Chengjie Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Immune Cells ◽  
Infarct Volume ◽  
Γδ T Cells ◽  
Neurological Deficits ◽  
Wild Type ◽  
Critical Function ◽  
Ischemic Brain ◽  
Potential Strategy

Perforin-mediated cytotoxicity plays a crucial role in microbial defense, tumor surveillance, and primary autoimmune disorders. However, the contribution of the cytolytic protein perforin to ischemia-induced secondary tissue damage in the brain has not been fully investigated. Here, we examined the kinetics and subpopulations of perforin-positive cells and then evaluated the direct effects of perforin-mediated cytotoxicity on outcomes after ischemic stroke. Using flow cytometry, we showed that perforin+CD45+ immune cells could be detected at 12 h and that the percentage of these cells increased largely until on day 3 and then significantly declined on day 7. Surprisingly, the percentage of Perforin+CD45+ cells also unexpectedly increased from day 7 to day 14 after ischemic stroke in Perforin1-EGFP transgenic mice. Our results suggested that Perforin+CD45+ cells play vital roles in the ischemic brain at early and late stages and further suggested that Perforin+CD45+ cells are a heterogeneous population. Surprisingly, in addition to CD8+ T cells, NK cells, and NKT cells, central nervous system (CNS)-resident immune microglia, which are first triggered and activated within minutes after ischemic stroke in mice, also secreted perforin during ischemic brain injury. In our study, the percentage of perforin+ microglia increased from 12 h after ischemic stroke, increased largely until on day 3 after ischemic stroke, and then moderately declined from days 3 to 7. Intriguingly, the percentage of perforin+ microglia also dramatically increased from days 7 to 14 after ischemic stroke. Furthermore, compared with wild-type littermates, Perforin 1–/– mice exhibited significant increases in the cerebral infarct volume, neurological deficits, and neurogenesis and inhibition of neurotoxic astrogliosis. Interestingly, the number of CD45+CD3+ T cells was significantly decreased in Perforin 1–/– mice compared with their wild-type littermates, especially the number of γδ T cells. In addition, Perforin 1–/– mice had lower levels of IL-17 than their wild-type littermates. Our results identified a critical function of perforin-mediated neurotoxicity in the ischemic brain, suggesting that targeting perforin-mediated neurotoxicity in brain-resident microglia and invading perforin+CD45+ immune cells may be a potential strategy for the treatment of ischemic stroke.

scholarly journals Neuroprotective effect of astrocyte-derived IL-33 in neonatal hypoxic-ischemic brain injury

2019 ◽  
Author(s):  
Mengya Jiao ◽  
Xiangyong Li ◽  
Xiaodi Wang ◽  
Liying Chen ◽  
Baohong Yuan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Injury ◽  
Neurotrophic Factor ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Brain Infarction ◽  
Neurological Deficits ◽  
Dependent Manner ◽  
Ischemic Brain

Abstract Background: Interleukin-33 (IL-33) is a well-recognized pleiotropic cytokine which plays crucial roles in immune regulation and inflammatory responses. Recent studies suggest that IL-33 and its receptor ST2 are involved in the pathogenesis of neurological diseases. Here, we explore the effect of IL-33/ST2 signaling in neonatal hypoxic-ischemic (HI) brain injury and elucidate the underlying mechanisms of action. Methods: The brain HI model was established in neonatal C57BL/6 mice by left common carotid artery occlusion with 90 min hypoxia, and treated with IL-33 at a dose of 0.2 μg/day i.p. for three days. TTC staining and neurobehavioral observation were used to evaluate the HI brain injury. Immunofluorescence and flow cytometry were applied to determine the expression of IL-33 and its receptor ST2 on brain CNS cells, cell proliferation and apoptosis. OGD experiment was used to assay the viability of astrocytes and neurons. RT-qPCR was used to measure the expression of neurotrophic factor-associated genes. Results: The expression level of IL-33 was markedly enhanced in astrocytes 24 h after cerebral HI in neonatal mice. Exogenous delivery of IL-33 significantly alleviated brain injury 7 d after HI, whereas ST2 deficiency exacerbated brain infarction and neurological deficits post HI. Flow cytometry analyses demonstrated high levels of ST2 expression on astrocytes, and the expression of ST2 was further elevated after HI. Intriguingly, IL-33 treatment apparently improved astrocyte response and attenuated HI-induced astrocyte apoptosis through ST2 signaling pathways. Further in vitro studies revealed that IL-33-activated astrocytes released a series of neurotrophic factors, which are critical for raising neuronal survival against oxygen glucose deprivation. Conclusions: The activation of IL-33/ST2 signaling in the ischemic brain improves astrocyte response, which in turn affords protection to ischemic neurons in a glial-derived neurotrophic factor-dependent manner.

scholarly journals Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 2938-2951 ◽  
Author(s):  
Yating He ◽  
Xiaofeng Ma ◽  
Daojing Li ◽  
Junwei Hao
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Bv2 Cells ◽  
Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

Glia Maturation Factor (GMF) Regulates Microglial Expression Phenotypes and the Associated Neurological Deficits in a Mouse Model of Traumatic Brain Injury

2020 ◽  
Vol 57 (11) ◽  
pp. 4438-4450 ◽  
Author(s):  
Mohammad Ejaz Ahmed ◽  
Govindhasamy Pushpavathi Selvakumar ◽  
Duraisamy Kempuraj ◽  
Sudhanshu P. Raikwar ◽  
Ramasamy Thangavel ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Mouse Model ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Maturation Factor

Reduction of ischemic brain injury in rats with normothermic and hyperthermic conditions

2008 ◽  
Vol 109 (3) ◽  
pp. 522-529 ◽  
Author(s):  
Alireza P. Shabanzadeh ◽  
Ashfaq Shuaib ◽  
Chen Xu Wang
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Cerebral Injury ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Injured Brain ◽  
Hyperthermic Condition ◽  
Bbb Permeability ◽  
Perfusion Deficits

Object Statins have been used for induction of ischemic tolerance after cerebral ischemia. The authors have previously shown that simvastatin is protective after ischemic cerebral injury in normothermic conditions. In this study they further examined whether treatment with simvastatin can reduce ischemic brain injury in a hyperthermic condition. Methods Focal ischemic brain injury was induced by embolizing a preformed clot into the middle cerebral artery in rats. The authors initially examined whether treatment with simvastatin could reduce ischemic brain injury without or with hyperthermia. The infarct volume, edema, and neurological deficits were examined. They then studied whether simvastatin could reduce the perfusion deficits, damage to the blood–brain barrier (BBB), and degeneration of neurons in the ischemic injured brain. Results Simvastatin significantly reduced the infarct volume in both normothermic and hyperthermic conditions, compared with appropriate controls. Concomitantly, this treatment also significantly reduced neurological deficits and brain edema. Administration of simvastatin significantly decreased perfusion deficits, BBB permeability, and degenerated neurons. Conclusions These studies suggest that simvastatin is an effective agent for ischemic brain injury not only in normothermic but also in hyperthermic conditions, which may be through the decrease of BBB permeability, degenerated neurons, and perfusion deficits.

Abstract W P220: Suppression of Interleukin 33 Limits Ischemic Brain Injury and Improves Functional Outcome in Murine Stroke Model

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Atif Zafar ◽  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Functional Outcome ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Interleukin 33 ◽  
The Brain

Background and purpose: Ischemic stroke is a leading cause of death and disability worldwide, and the treatment options are limited. Interleukin-33 (IL-33) is a newly recognized IL-1 family cytokine which signals via its ST2 receptor, and acts as a key regulator of inflammation. However, the expression of IL-33 in the brain was not well studied and its expression in ischemic stroke remains to be elucidated. In the present study, we measured IL-33 and ST2 levels and examine the correlation of IL-33 expression with brain damage and functional outcome following ischemic stroke. Methods: IL-33 expression was examined in ischemic brain hemisphere. Mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hr using a filament model, followed by 23 hrs reperfusion. Briefly, mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the estimation of IL-33 and ST2 expression. Expression of IL-33 and its receptor ST2 was monitored by ELISA, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, expression of NF-kB and proinflammatory cytokines were evaluated after ischemia/reperfusion. Results: We found significantly increased expression level of IL-33 and ST2 in the MCAO mice as compare to the saline treated control mice. Moreover, treating the MCAO mice with recombinant IL-33 increases the brain injury and worsens neurological deficits in MCAO mice as compare to control mice. Interestingly, increased ischemic brain damage and neurological deficits were largely abrogated in mice treated with IL-33 neutralizing antibody. Conclusion: These findings provide the first evidence that IL-33/ST2 signaling plays an important role in the pathogenesis of stroke. Moreover, IL-33 exacerbates inflammatory brain injury after ischemic stroke and treatment with specific IL-33 neutralizing antibody inhibited the ischemic brain injury. Therefore, blocking the IL-33 may represent an efficient therapy in stroke.

Abstract 3856: Adoptive Transfer Of Regulatory T Cells Confers Long Term Neuroprotection Against Cerebral Ischemic Stroke

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Peiying Li ◽  
Xiaoming Hu ◽  
Yu Gan ◽  
Feng Zhang ◽  
Yanqin Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Infarct Volume ◽  
The Body ◽  
Neurological Deficits ◽  
Adoptive Therapy ◽  
Ischemic Brain ◽  
Cell Based Therapy

Stroke is the leading cause of serious long-term disability in adults. Activation and mobilization of CD4+CD25+ regulatory T cells (Tregs) is an intrinsic mechanism the body uses to restrict pro-inflammatory response, one of the well-established contributing factors for secondary neuronal injury and long-term neurological deficits after stroke. The current study explores the protective effect of Tregs adoptive therapy against post-ischemic brain damage and investigated the mechanisms underlying the action of Tregs. Using a mouse model of focal transient ischemia, we found that intravenous injections of Tregs (2 x 10 6 /animal) within 24 hours (2, 6, and 24 hours) after ischemia resulted in marked reduction of brain infarct. The maximal protection occurred upon earlier Tregs transfer with 2-hour delay after MCAO, which resulted in approximately 30% reduction of infarct volume. Post-ischemic sensorimotor dysfunction significantly improved during both the acute and late recovery after MCAO in Treg-treated mice as assessed by corner test, forelimb placing and cylinder test up to 28 days after ischemic stroke. Furthermore, Tregs treatment inhibited the up-regulation of IL-6, IL-1β, IL-17 and TNF-α in the ischemic brain and mitigated the cerebral infiltration of peripheral immune cells, including neutrophil, macrophage and T cells early after MCAO. Taken together, our study demonstrates that adoptive therapy with Tregs is a novel and potent cell-based therapy targeting post-stroke inflammatory dysregulation.

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