A novel approach to treatment of thromboembolic stroke in mice: Redirecting neutrophils toward a peripherally implanted CXCL1-soaked sponge

Stamatovic, Svetlana M.; Phillips, Chelsea; Keep, Richard F.; Andjelkovic, Anuska V.

doi:10.1016/j.expneurol.2020.113336

Cited by 18 publications

(11 citation statements)

References 59 publications

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“…Clinical study has revealed that leukocyte and neutrophil counts are increased on the first day after acute ischemic stroke 24 . Accordingly, reducing neutrophil in peripheral blood could improve stroke outcomes 25 . Cerebral ischemia leads to augmentation of brain infiltration and activation of neutrophils and lymphocytes in type 2 diabetic mice 26 .…”

Section: Discussionmentioning

confidence: 99%

“…CCL‐4 induces lymphocytes transmigration to neurovascular barrier disruption 50 . CXCL1, as a neutrophil‐specific chemokine, improves neurological outcomes in experimental ischemic stroke 25 . To explore molecular mechanisms of leukocyte‐endothelial cell interactions and the inhibitory effects of TXL on the interactions after recanalization in stroke, adhesion molecules, and chemokines in plasma and brain were measured by CBA at 24 h and 72 h after tMCAO.…”

Section: Discussionmentioning

confidence: 99%

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Inhibiting leukocyte‐endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no‐reflow after arterial recanalization in ischemic stroke

Liu

Zhang

et al. 2023

CNS Neurosci Ther

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AimsDespite successful vascular recanalization in stroke, one‐fourth of patients have an unfavorable outcome due to no‐reflow. The pathogenesis of no‐reflow is fully unclear, and therapeutic strategies are lacking. Upon traditional Chinese medicine, Tongxinluo capsule (TXL) is a potential therapeutic agent for no‐reflow. Thus, this study is aimed to investigate the pathogenesis of no‐reflow in stroke, and whether TXL could alleviate no‐reflow as well as its potential mechanisms of action.MethodsMice were orally administered with TXL (3.0 g/kg/d) after transient middle cerebral artery occlusion. We examined the following parameters: neurological function, no‐reflow, leukocyte‐endothelial cell interactions, HE staining, leukocyte subtypes, adhesion molecules, and chemokines.ResultsOur results showed stroke caused neurological deficits, neuron death, and no‐reflow. Adherent and aggregated leukocytes obstructed microvessels as well as leukocyte infiltration in ischemic brain. Leukocyte subtypes changed after stroke mainly including neutrophils, lymphocytes, regulatory T cells, suppressor T cells, helper T type 1 (Th1) cells, Th2 cells, B cells, macrophages, natural killer cells, and dendritic cells. Stroke resulted in upregulated expression of adhesion molecules (P‐selectin, E‐selectin, and ICAM‐1) and chemokines (CC‐chemokine ligand (CCL)‐2, CCL‐3, CCL‐4, CCL‐5, and chemokine C‐X‐C ligand 1 (CXCL‐1)). Notably, TXL improved neurological deficits, protected neurons, alleviated no‐reflow and leukocyte‐endothelial cell interactions, regulated multiple leukocyte subtypes, and inhibited the expression of various inflammatory mediators.ConclusionLeukocyte‐endothelial cell interactions mediated by multiple inflammatory factors are an important cause of no‐reflow in stroke. Accordingly, TXL could alleviate no‐reflow via suppressing the interactions through modulating various leukocyte subtypes and inhibiting the expression of multiple inflammatory mediators.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibiting leukocyte‐endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no‐reflow after arterial recanalization in ischemic stroke

Liu

Zhang

et al. 2023

CNS Neurosci Ther

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“…Thromboembolic (TE) stroke was induced by injecting a platelet-rich microemboli suspension (particle size ~ 4 µm) as described previously [ 45 , 46 ]. Briefly, a thromboemboli suspension was prepared by mixing arterial blood with thrombin solution [60 U thrombin (Sigma Aldrich, St Louis, MO USA) in 0.9% NaCl) at a ratio of 4:1.…”

Section: Methodsmentioning

confidence: 99%

Epigenetics and stroke: role of DNA methylation and effect of aging on blood–brain barrier recovery

Phillips

Stamatovic

Keep

et al. 2023

Fluids Barriers CNS

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Incomplete recovery of blood–brain barrier (BBB) function contributes to stroke outcomes. How the BBB recovers after stroke remains largely unknown. Emerging evidence suggests that epigenetic factors play a significant role in regulating post-stroke BBB recovery. This study aimed to evaluate the epigenetic and transcriptional profile of cerebral microvessels after thromboembolic (TE) stroke to define potential causes of limited BBB recovery. RNA-sequencing and reduced representation bisulfite sequencing (RRBS) analyses were performed using microvessels isolated from young (6 months) and old (18 months) mice seven days poststroke compared to age-matched sham controls. DNA methylation profiling of poststroke brain microvessels revealed 11,287 differentially methylated regions (DMR) in old and 9818 DMR in young mice, corresponding to annotated genes. These DMR were enriched in genes encoding cell structural proteins (e.g., cell junction, and cell polarity, actin cytoskeleton, extracellular matrix), transporters and channels (e.g., potassium transmembrane transporter, organic anion and inorganic cation transporters, calcium ion transport), and proteins involved in endothelial cell processes (e.g., angiogenesis/vasculogenesis, cell signaling and transcription regulation). Integrated analysis of methylation and RNA sequencing identified changes in cell junctions (occludin), actin remodeling (ezrin) as well as signaling pathways like Rho GTPase (RhoA and Cdc42ep4). Aging as a hub of aberrant methylation affected BBB recovery processes by profound alterations (hypermethylation and repression) in structural protein expression (e.g., claudin-5) as well as activation of a set of genes involved in endothelial to mesenchymal transformation (e.g., Sox9, Snai1), repression of angiogenesis and epigenetic regulation. These findings revealed that DNA methylation plays an important role in regulating BBB repair after stroke, through regulating processes associated with BBB restoration and prevalently with processes enhancing BBB injury.

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“…Recently, a novel strategy to redirect neutrophils from the ischemic brain to the periphery by peripherally implanting a CXCL1-soaked sponge led to improved neurological performance and infarction by reducing neutrophil-induced inflammation ( 219 ). Platelet-mimetic nanoparticles (PTNPs) were co-loaded with superparamagnetic iron oxide (SPIO), a T2 contrast agent.…”

Section: Immunotherapies Targeting Bbb Disruption During Ischemic Strokementioning

confidence: 99%

Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?

et al. 2021

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Blood-Brain Barrier (BBB) disruption is an important pathophysiological process of acute ischemic stroke (AIS), resulting in devastating malignant brain edema and hemorrhagic transformation. The rapid activation of immune cells plays a critical role in BBB disruption after ischemic stroke. Infiltrating blood-borne immune cells (neutrophils, monocytes, and T lymphocytes) increase BBB permeability, as they cause microvascular disorder and secrete inflammation-associated molecules. In contrast, they promote BBB repair and angiogenesis in the latter phase of ischemic stroke. The profound immunological effects of cerebral immune cells (microglia, astrocytes, and pericytes) on BBB disruption have been underestimated in ischemic stroke. Post-stroke microglia and astrocytes can adopt both an M1/A1 or M2/A2 phenotype, which influence BBB integrity differently. However, whether pericytes acquire microglia phenotype and exert immunological effects on the BBB remains controversial. Thus, better understanding the inflammatory mechanism underlying BBB disruption can lead to the identification of more promising biological targets to develop treatments that minimize the onset of life-threatening complications and to improve existing treatments in patients. However, early attempts to inhibit the infiltration of circulating immune cells into the brain by blocking adhesion molecules, that were successful in experimental stroke failed in clinical trials. Therefore, new immunoregulatory therapeutic strategies for acute ischemic stroke are desperately warranted. Herein, we highlight the role of circulating and cerebral immune cells in BBB disruption and the crosstalk between them following acute ischemic stroke. Using a robust theoretical background, we discuss potential and effective immunotherapeutic targets to regulate BBB permeability after acute ischemic stroke.

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A novel approach to treatment of thromboembolic stroke in mice: Redirecting neutrophils toward a peripherally implanted CXCL1-soaked sponge

Cited by 18 publications

References 59 publications

Inhibiting leukocyte‐endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no‐reflow after arterial recanalization in ischemic stroke

Inhibiting leukocyte‐endothelial cell interactions by Chinese medicine Tongxinluo capsule alleviates no‐reflow after arterial recanalization in ischemic stroke

Epigenetics and stroke: role of DNA methylation and effect of aging on blood–brain barrier recovery

Immune Cells in the BBB Disruption After Acute Ischemic Stroke: Targets for Immune Therapy?

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