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

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Июнь 23, 2021

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

Язык: Английский

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Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice

Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)

Опубликована: Июнь 11, 2022

Neuronal pyroptosis and neuroinflammation with excess microglial activation are widely involved in the early pathological process of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulatory technique, has recently been reported to be anti-inflammatory regulate function. However, few studies have elucidated role mechanism rTMS underlying regulating neuronal polarization.We evaluated motor function middle cerebral artery occlusion/reperfusion (MCAO/r) injury mice after 1-week intermittent theta-burst (iTBS) treatment phase or without depletion microglia by colony-stimulating factor 1 receptor (CSF1R) inhibitor treatment, respectively. We further explored morphological molecular biological alterations associated polarization via Nissl, EdU, TTC, TUNEL staining, electron microscopy, multiplex cytokine bioassays, western blot assays, immunofluorescence staining RNA sequencing.ITBS significantly protected against ischemia/reperfusion (I/R) injury-induced locomotor deficits damage, which probably relied on regulation innate immune inflammatory responses, evidenced sequencing analysis. The peak was confirmed later than that apoptosis during stroke, mainly located more severe peri-infarcted area compared apoptosis. Multiplex bioassays showed iTBS ameliorated high levels IL-1β, IL-17A, TNF-α, IFN-γ MCAO/r group elevated level IL-10. ITBS inhibited expression pyroptosis-associated proteins (i.e., Caspase1, IL-18, ASC, GSDMD, NLRP1) rather at border infarcted core. KEGG enrichment analysis demonstrated shifted M1/M2 phenotype balance curbing proinflammatory M1 (Iba1+/CD86+) enhancing M2 (Iba1+/CD206+) inhibiting TLR4/NFκB/NLRP3 signaling pathway. Depletion using CSF1R (PLX3397) eliminated functional improvements treatment.rTMS could alleviate I/R induced modulating polarization. It is expected these data will provide novel insights into mechanisms protecting potential targets

Язык: Английский

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M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice

Theranostics, Год журнала: 2022, Номер 12(7), С. 3553 - 3573

Опубликована: Янв. 1, 2022

Rationale: White matter repair is critical for the cognitive and neurological functional recovery after ischemic stroke.M2 microglia are well-documented to enhance remyelination their extracellular vesicles (EVs) mediate cellular function brain injury.However, whether M2 microglia-derived EVs could promote white cerebral ischemia its underlying mechanism largely unknown.Methods: were isolated from IL-4 treated (M2-EVs) untreated (M0-EVs).Adult ICR mice subjected 90-minute transient middle artery occlusion received intravenous treatment seven consecutive days.Brain atrophy volume, neurobehavioral tests examined within 28 days following ischemia.Immunohistochemistry, myelin transmission electron microscope compound action potential measurement performed assess structural remodeling, oligodendrogenesis.The effects of M2-EVs on oligodendrocyte precursor cells (OPCs) also in vitro.EVs' miRNA sequencing, specific miR-23a-5p knockdown luciferase reporter assay used explore mechanism.Results: reduced promoted recovery, oligodendrogenesis vivo, increased OPC proliferation, survival differentiation vitro.miR-23a-5p was enriched maturation, while knocking down reversed beneficial both vitro vivo.Luciferase showed that directly targeted Olig3.Conclusion: Our results demonstrated communicate OPCs through via possibly by targeting Olig3 stroke, suggesting a novel promising therapeutic strategy stroke demyelinating disease.

Язык: Английский

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Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones

Biomolecules, Год журнала: 2024, Номер 14(3), С. 305 - 305

Опубликована: Март 4, 2024

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital the successful development clinically useful medications. Stroke is generally accepted as leading cause adult disability globally and ischemic stroke accounts most common form two main types. Despite its health socioeconomic burden, there still minimal availability effective pharmacological treatment. In this review, we take an in-depth look at etiology stroke, including molecular cellular changes. This followed by a highlight drugs, therapies, complementary medicines that or undergoing clinical trials treatment management stroke. We also identify unexplored potential targets in pathogenesis can be exploited increase pool anti-stroke neuroprotective agents through de novo drug repurposing.

Язык: Английский

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Mechanisms of immune response and cell death in ischemic stroke and their regulation by natural compounds

Frontiers in Immunology, Год журнала: 2024, Номер 14

Опубликована: Янв. 11, 2024

Ischemic stroke (IS), which is the third foremost cause of disability and death worldwide, has inflammation cell as its main pathological features. IS can lead to neuronal release factors such damage-related molecular patterns, stimulating immune system inflammatory mediators, thereby resulting in exacerbating brain damage. Currently, there are a limited number treatment methods for IS, fact necessitating discovery new targets. For this review, current research on ischemic was summarized. The complex roles pathways principal cells (microglia, astrocyte, neutrophils, T lymphocytes, monocytes/macrophage) after discussed. mechanisms interactions cytokines involved these Moreover, (pyroptosis, apoptosis, necroptosis, PANoptosis, ferroptosis) explored. Finally, summary provided mechanism action natural pharmacological active ingredients IS. Despite significant recent progress remain many challenges that need be overcome.

Язык: Английский

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Glaucoma: from pathogenic mechanisms to retinal glial cell response to damage

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Янв. 25, 2024

Glaucoma is a neurodegenerative disease of the retina characterized by irreversible loss retinal ganglion cells (RGCs) leading to visual loss. Degeneration RGCs and their axons, as well damage remodeling lamina cribrosa are main events in pathogenesis glaucoma. Different molecular pathways involved RGC death, which triggered exacerbated consequence number risk factors such elevated intraocular pressure (IOP), age, ocular biomechanics, or low perfusion pressure. Increased IOP one most important associated with this pathology only for treatment currently available, nevertheless, on many cases progression continues, despite control. Thus, elevation not trigger glaucomatous damage, showing evidence that other can induce death pathology, would be advance neurodegeneration. The underlying mechanisms driving process glaucoma include ischemia/hypoxia, mitochondrial dysfunction, oxidative stress neuroinflammation. In glaucoma, like disorders, immune system immunoregulation conducted mainly glial cells, microglia, astrocytes, Müller cells. increase produces activation tissue. Chronic may provoke proinflammatory state at level inducing blood barrier disruption death. modulation response constitute an interesting new approach

Язык: Английский

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The natural (poly)phenols as modulators of microglia polarization via TLR4/NF-κB pathway exert anti-inflammatory activity in ischemic stroke

European Journal of Pharmacology, Год журнала: 2021, Номер 914, С. 174660 - 174660

Опубликована: Дек. 1, 2021

Язык: Английский

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The roles of microglia and astrocytes in myelin phagocytosis in the central nervous system

Journal of Cerebral Blood Flow & Metabolism, Год журнала: 2022, Номер 43(3), С. 325 - 340

Опубликована: Ноя. 2, 2022

Myelination is an important process in the central nervous system (CNS). Oligodendrocytes (OLs) extend multiple layers to densely sheath on axons, composing myelin achieve efficient electrical signal conduction. The myelination during developmental stage maintains a balanced state. However, numerous CNS diseases including neurodegenerative and cerebrovascular cause demyelination disrupt homeostasis, resulting inflammation white matter deficits. Effective clearance of debris needed region demyelination, which key step for remyelination tissue regeneration. Microglia astrocytes are major resident phagocytic cells brain, may play different or collaborative roles myelination. participate through engulfing excessive unneeded myelin. They also involved degenerated accelerating remyelination, healthy inhibiting remyelination. This review focuses microglia phagocytosing brain diseased brain. In addition, interaction between mediate engulfment summarized.

Язык: Английский

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Tat-NTS peptide protects neurons against cerebral ischemia-reperfusion injury via ANXA1 SUMOylation in microglia

Theranostics, Год журнала: 2023, Номер 13(15), С. 5561 - 5583

Опубликована: Янв. 1, 2023

Rationale:Recent studies indicate that microglial activation and the resulting inflammatory response could be potential targets of adjuvant therapy for ischemic stroke.Many have emphasized a well-established function Annexin-A1 (ANXA1) in immune system, including regulation activation.Nevertheless, few therapeutic interventions targeting ANXA1 microglia stroke been conducted.In present study, Tat-NTS, small peptide developed to prevent from entering nucleus, was utilized.We discovered underlying mechanism Tat-NTS protect against brain injury.Methods: Preclinical were performed using an oxygen-glucose deprivation reperfusion (OGD/R) cell model vitro middle cerebral artery occlusion (MCAO) animal vivo.Confocal imaging 3D reconstruction analyses detecting protein expression subcellular localization vivo.Co-immunoprecipitation (Co-IP), immunoblotting, ELISA, quantitative real-time PCR (qRT-PCR), Luciferase reporter assay determining precise molecular mechanism.Measurement on cytotoxicity assessed by CCK-8 LDH assay.TUNEL staining used detect conditioned medium-mediated neuronal apoptosis.Adeno-associated viruses (AAVs) injected into cortex, striatum hippocampal CA1 region adult male Cx3cr1-Cre mice, further verify neurofunctional outcome TTC staining, modified Neurological Severity Score (mNSS) test, open field test (OFT), novel object recognition task (NORT), Morris water maze (MWM) long-term potentiation (LTP) Transmission electron microscopy (TEM). Results:It observed administration led shift nucleus cytoplasm injury.Notably, this accompanied increase SUMOylation transformation towards anti-inflammatory phenotype.We confirmed Tat-NTS-induced mediated IKKα degradation via NBR1-dependent selective autophagy, then blocking NF-κB pathway.As result, release pro-inflammatory factors IL-1β TNF-α reduced both vivo experiments.Furthermore, we found peptide's protective effect relieved neuron apoptosis.Finally, Ivyspring

Язык: Английский

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Chronic kidney disease promotes cerebral microhemorrhage formation

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Фев. 25, 2023

Abstract Background Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular not well-understood. We investigated the development of cerebral small vessel using in vivo and vitro models CKD. Methods CKD was produced aged C57BL/6J mice an adenine-induced tubulointerstitial nephritis model. analyzed brain histology Prussian blue staining to examine formation microhemorrhage (CMH), hemorrhagic component neuropathological substrate MRI-demonstrable microbleeds. In cell culture studies, we examined effects serum from healthy or patients gut-derived uremic toxins on microvascular endothelial barrier. Results induced significant increases both creatinine cystatin C levels ( p < 0.0001) without elevation systolic diastolic blood pressure. CMH significantly increased positively correlated level (Spearman r = 0.37, 0.01). Moreover, Iba-1-positive immunoreactivity by 51% 0.001), phenotypic switch resting activated microglia, enhanced fibrinogen extravasation across blood–brain barrier (BBB) 34% 0.05). On analysis stratified sex, increase number more pronounced male this greater compared female mice. Microglial depletion PLX3397 diet decreased affecting levels. Incubation reduced transendothelial electrical resistance (TEER) 0.01) sodium fluorescein permeability 0.05) monolayer. Uremic (i.e., indoxyl sulfate, p-cresyl trimethylamine-N-oxide) combination urea lipopolysaccharide marked drop TEER control group 0.0001). Conclusions promotes independent pressure directly proportional degree renal impairment. These are likely mediated part microglia associated BBB The latter related bacteria-dependent classically Overall, these findings demonstrate important role disease.

Язык: Английский

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