scholarly journals CD28 Superagonist-Mediated Boost of Regulatory T Cells Increases Thrombo-Inflammation and Ischemic Neurodegeneration during the Acute Phase of Experimental Stroke

2014 ◽  
Vol 35 (1) ◽  
pp. 6-10 ◽  
Author(s):  
Michael K Schuhmann ◽  
Peter Kraft ◽  
Guido Stoll ◽  
Kristina Lorenz ◽  
Sven G Meuth ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Thrombus Formation ◽  
Inflammatory Lesion ◽  
Artery Occlusion ◽  
Acute Stage ◽  
Experimental Stroke ◽  
Cerebral Artery Occlusion

While the detrimental role of non-regulatory T cells in ischemic stroke is meanwhile unequivocally recognized, there are controversies about the properties of regulatory T cells (Treg). The aim of this study was to elucidate the role of Treg by applying superagonistic anti-CD28 antibody expansion of Treg. Stroke outcome, thrombus formation, and brain-infiltrating cells were determined on day 1 after transient middle cerebral artery occlusion. Antibody-mediated expansion of Treg enhanced stroke size and worsened functional outcome. Mechanistically, Treg increased thrombus formation in the cerebral microvasculature. These findings confirm that Treg promote thrombo-inflammatory lesion growth during the acute stage of ischemic stroke.

Coming to the Rescue: Regulatory T Cells for Promoting Recovery After Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (12) ◽  
Author(s):  
Yueman Zhang ◽  
Arthur Liesz ◽  
Peiying Li
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Immune Cell ◽  
Inflammatory Lesion ◽  
Experimental Stroke ◽  
Immune Cell Population ◽  
Neuroinflammatory Response ◽  
Mediated Effects ◽  
Injured Brain

Immune cell infiltration to the injured brain is a key component of the neuroinflammatory response after ischemic stroke. In contrast to the large amount of proinflammatory immune cells, regulatory T cells, are an important subgroup of T cells that are involved in maintaining immune homeostasis and suppress an overshooting immune reaction after stroke. Numerous previous reports have consistently demonstrated the beneficial role of this immunosuppressive immune cell population during the acute phase after experimental stroke by limiting inflammatory lesion progression. Two recent studies expanded now this concept and demonstrate that regulatory T cells-mediated effects also promote chronic recovery after stroke by promoting a proregenerative tissue environment. These recent findings suggest that boosting regulatory T cells could be beneficial beyond modulating the immediate neuroinflammatory response and improve chronic functional recovery.

scholarly journals Phospholipase D1 and D2 Synergistically Regulate Thrombus Formation

2020 ◽  
Vol 21 (18) ◽  
pp. 6954
Author(s):  
Li-Ming Lien ◽  
Wan-Jung Lu ◽  
Ting-Yu Chen ◽  
Tzu-Yin Lee ◽  
Hsueh-Hsiao Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Thrombus Formation ◽  
Artery Occlusion ◽  
Pulmonary Thrombosis ◽  
Neurological Severity Score ◽  
Phospholipase D1 ◽  
Redundant Functions ◽  
Cerebral Artery Occlusion ◽  
Increase Survival Rate

Previously, we reported that phospholipase D1 (PLD1) and PLD2 inhibition by selective PLD1 and PLD2 inhibitors could prevent platelet aggregation in humans, but not in mice. Moreover, only the PLD1 inhibitor, but not PLD2 inhibitor, could effectively prevent thrombus formation in mice, indicating that PLD might play different roles in platelet function in humans and mice. Although PLD1 and PLD2 were reported to be implicated in thrombotic events, the role of PLD in mice remains not completely clear. Here, we investigated the role of PLD1 and PLD2 in acute pulmonary thrombosis and transient middle cerebral artery occlusion-induced brain injury in mice. The data revealed that inhibition of PLD1, but not of PLD2, could partially prevent pulmonary thrombosis-induced death. Moreover, concurrent PLD1 and PLD2 inhibition could considerably increase survival rate. Likewise, inhibition of PLD1, but not PLD2, partially improved ischemic stroke and concurrent inhibition of PLD1, and PLD2 exhibited a relatively better protection against ischemic stroke, as evidenced by the infarct size, brain edema, modified neurological severity score, rotarod test, and the open field test. In conclusion, PLD1 might play a more important role than PLD2, and both PLD1 and PLD2 could act synergistically or have partially redundant functions in regulating thrombosis-relevant events.

scholarly journals Infarct Growth Precedes Cerebral Thrombosis Following Experimental Stroke in Mice

2021 ◽  
Author(s):  
Vanessa Göb ◽  
Maximilian G. Voll ◽  
Lena Zimmermann ◽  
Katherina Hemmen ◽  
Guido Stoll ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tissue Damage ◽  
Thrombus Formation ◽  
Brain Slices ◽  
Light Sheet ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Cerebral Thrombosis ◽  
Cerebral Artery Occlusion ◽  
Kinetics Of

Abstract Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.

scholarly journals Infarct growth precedes cerebral thrombosis following experimental stroke in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Vanessa Göb ◽  
Maximilian G. Voll ◽  
Lena Zimmermann ◽  
Katherina Hemmen ◽  
Guido Stoll ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tissue Damage ◽  
Thrombus Formation ◽  
Brain Slices ◽  
Light Sheet ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Cerebral Thrombosis ◽  
Cerebral Artery Occlusion ◽  
Kinetics Of

AbstractIschemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.

scholarly journals Treatment Effects of Ischemic Stroke by Berberine, Baicalin, and Jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) Explored by an Integrated Metabolomics Approach

2017 ◽  
Vol 2017 ◽  
pp. 1-20 ◽  
Author(s):  
Qian Zhang ◽  
Xiaowei Fu ◽  
Junsong Wang ◽  
Minghua Yang ◽  
Lingyi Kong
Keyword(s):  
Ischemic Stroke ◽  
Treatment Effects ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
H Nmr ◽  
Abnormal Metabolism ◽  
Cerebral Artery Occlusion ◽  
First Time ◽  
Integrated Metabolomics

Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian-Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the 1H NMR metabolomics approach was used to assess the metabolic profiles, which combined with correlation network analysis successfully revealed metabolic disorders in ischemic stroke concerning the treatment of the three principal compounds from HLJDD for the first time. The combined results suggested that berberine, baicalin, and jasminoidin are responsible for the effectiveness of HLJDD on the treatment of ischemic stroke by amelioration of abnormal metabolism and regulation of oxidative stress, neuron autophagy, and inflammatory response. This integrated metabolomics approach showed its potential in understanding the function of complex formulae and clarifying the role of its components in the overall treatment effects.

scholarly journals Regulatory T cells participate in the recovery of ischemic stroke patients

2020 ◽  
Author(s):  
María Santamaría-Cadavid ◽  
Emilio Rodríguez-Castro ◽  
Manuel Rodríguez-Yáñez ◽  
Susana Arias-Rivas ◽  
Iria López-Dequidt ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Functional Outcome ◽  
Infarct Volume ◽  
Control Subjects ◽  
Good Functional Outcome ◽  
Early Neurological Deterioration ◽  
The Relationship

Abstract Background: Recent preclinical studies have shown that regulatory T cells (Treg) play a key role in the immune response after ischemic stroke (IS). However, the role of Treg in human acute IS has been poorly investigated. Our aim was to study the relationship between circulating Treg and outcome in human IS patients. Methods: A total of 204 IS patients and 22 control subjects were recruited. The main study variable was good functional outcome at 3 months (modified Rankin scale ≤2) considering infarct volume, Early Neurological Deterioration (END) and risk of infections as secondary variables. The percentage of circulating Treg was measured at admission, 48, 72h and at day 7 after stroke onset. Results: Circulating Treg levels were higher in IS patients compared to control subjects. Treg at 48h were independently associated with good functional outcome (OR, 3.5; CI: 1.9-7.8) after adjusting by confounding factors. Patients with lower Treg at 48h showed higher frequency of END and risk of infections. In addition, a negative correlation was found between circulating Treg at 48h (r=-0.414) and 72h (r=-0.418) and infarct volume. Conclusions: These findings suggest that Treg may participate in the recovery of IS patients. Therefore, Treg may be considered a potential therapeutic target in acute ischemic stroke.

scholarly journals Interleukin 1 alpha administration is neuroprotective and neuro-restorative following experimental ischemic stroke

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Kathleen E. Salmeron ◽  
Michael E. Maniskas ◽  
Danielle N. Edwards ◽  
Raymond Wong ◽  
Ivana Rajkovic ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Side Effects ◽  
Carotid Artery ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Interleukin 1 ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion

Abstract Background Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016). Methods Transient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22–27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses. Results We now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair. Conclusions Taken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.

scholarly journals Delayed Reperfusion Deficits after Experimental Stroke Account for Increased Pathophysiology

2014 ◽  
Vol 35 (2) ◽  
pp. 277-284 ◽  
Author(s):  
Fiona E Burrows ◽  
Natasha Bray ◽  
Adam Denes ◽  
Stuart M Allan ◽  
Ingo Schiessl
Keyword(s):  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Therapeutic Interventions ◽  
Experimental Stroke ◽  
Initial Increase ◽  
Significant Drop ◽  
Sham Surgery ◽  
Interleukin 1Α ◽  
Oxygen Perfusion ◽  
Cerebral Artery Occlusion

Cerebral blood flow and oxygenation in the first few hours after reperfusion following ischemic stroke are critical for therapeutic interventions but are not well understood. We investigate changes in oxyhemoglobin (HbO2) concentration in the cortex during and after ischemic stroke, using multispectral optical imaging in anesthetized mice, a remote filament to induce either 30 minute middle cerebral artery occlusion (MCAo), sham surgery or anesthesia alone. Immunohistochemistry establishes cortical injury and correlates the severity of damage with the change of oxygen perfusion. All groups were imaged for 6 hours after MCAo or sham surgery. Oxygenation maps were calculated using a pathlength scaling algorithm. The MCAo group shows a significant drop in HbO2 during occlusion and an initial increase after reperfusion. Over the subsequent 6 hours HbO2 concentrations decline to levels below those observed during stroke. Platelets, activated microglia, interleukin-1α, evidence of BBB breakdown and neuronal stress increase within the stroked hemisphere and correlate with the severity of the delayed reperfusion deficit but not with the ΔHbO2 during stroke. Despite initial restoration of HbO2 after 30 min MCAo there is a delayed compromise that coincides with inflammation and could be a target for improved stroke outcome after thrombolysis.

scholarly journals Estradiol Attenuates Neuroprotective Benefits of Isoflurane Preconditioning in Ischemic Mouse Brain

2008 ◽  
Vol 28 (11) ◽  
pp. 1824-1834 ◽  
Author(s):  
Lan Wang ◽  
Hideto Kitano ◽  
Patricia D Hurn ◽  
Stephanie J Murphy
Keyword(s):  
Infarct Volume ◽  
Artery Occlusion ◽  
Experimental Stroke ◽  
Ischemic Damage ◽  
Triphenyltetrazolium Chloride ◽  
Anesthetic Preconditioning ◽  
Infarction Volume ◽  
Male Specific ◽  
Cerebral Artery Occlusion

Isoflurane preconditioning (IsoPC) neuroprotection in experimental stroke is male-specific. We determined whether estradiol alters ischemic outcomes in IsoPC brain and examined the role of estrogen receptors (ERs). Seven to 10 days before preconditioning, ovariectomized (OVX) mice were implanted with estradiol, vehicle, or ER subtype agonists. OVX ± estradiol, OVX ± vehicle, OVX ± ER agonists, and ER subtype wild-type (WT) and knockout (KO) mice were preconditioned for 4 h with sham anesthetic preconditioning (sham PC) or 1% IsoPC and recovered for 24 h. Mice then underwent 2 h of middle cerebral artery occlusion followed by 22 h of reperfusion. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining, with comparisons between IsoPC and corresponding sham PC for each treatment group. Decreased infarct injury was seen in IsoPC OVX ± vehicle, whereas estradiol in IsoPC OVX mice enhanced ischemic damage. In ER studies, increased infarct volumes were seen in IsoPC ERWT mice regardless of ER subtype. IsoPC in ERαKO mice had no effect on infarction volume but reduced only cortical ischemic damage in ERβKO mice. In OVX + ERβ agonist, IsoPC had no effect on infarction volume. In OVX + ER/α agonist, IsoPC increased cortical infarct volume. Estradiol depresses the brain's protective response to IsoPC and may exacerbate cortical ischemic injury mainly through an ERβ-dependent mechanism.

scholarly journals The Paradox Role of Regulatory T Cells in Ischemic Stroke

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaomeng Xu ◽  
Min Li ◽  
Yongjun Jiang
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Microvascular Dysfunction ◽  
Underlying Mechanism ◽  
Pathophysiological Process ◽  
Function Recovery ◽  
Current Lines ◽  
Lines Of Evidence

The underlying mechanism of ischemic stroke is not completely known. Regulatory T cells (Tregs), a subset of T cells, play a pivotal role in the pathophysiological process of ischemic stroke. However, there is also controversy over the role of Tregs in stroke. Hence, the function of Tregs in ischemic stroke has triggered a heated discussion recently. In this paper, we reviewed the current lines of evidence to describe the full view of Tregs in stroke. We would like to introduce the basic concepts of Tregs and then discuss their paradox function in ischemic stroke. On one side, Tregs could protect brain against ischemic injury via modulating the inflammation process. On the other side, they exaggerated the insult by causing microvascular dysfunction. They also interfered with the neurological function recovery. In addition, the reasons for this paradox role would be discussed in the review and the prospective of the clinical application of Tregs was also included. In conclusion, Tregs contributed to the outcome of ischemic stroke, while more lines of evidence are needed to understand how Tregs regulate the immune system and influence the outcome of stroke.

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