Microglia at the blood brain barrier in health and disease

Frontiers in Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: March 13, 2024

The blood brain barrier (BBB) plays a crucial role in maintaining homeostasis by selectively preventing the entry of substances from peripheral into central nervous system (CNS). Comprised endothelial cells, pericytes, and astrocytes, this highly regulated encompasses majority brain’s vasculature. In addition to its protective function, BBB also engages significant crosstalk with perivascular macrophages (MΦ) microglia, resident MΦ brain. These interactions play pivotal modulating activation state cells comprising BBB, as well MΦs themselves. Alterations systemic metabolic inflammatory states can promote cell dysfunction, reducing integrity potentially allowing factors leak CNS compartment. This may mediate MΦs, initiate further immune responses within parenchyma, suggesting neuroinflammation be triggered signaling periphery, without primary injury or disease originating CNS. intricate interplay between periphery through highlights importance understanding microglia mediating challenges. Despite recent advancements, our is still early stages, leaving gap knowledge. However, emerging research shedding light on involvement at various conditions, including infections, diabetes, ischemic stroke. review aims provide comprehensive overview current investigating relationship health disease. By exploring these connections, we hope advance challenges their impact pathology. Uncovering hold promise for development novel therapeutic strategies neurological conditions that involve vascular mechanisms.

Language: Английский

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Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(7)

Published: Feb. 14, 2025

Poststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is considered a marker for anti-inflammatory macrophages, associated with the resolution of and promotion tissue repair in various pathological conditions. However, its specific role poststroke recovery remains to be elucidated. This study investigates impact Arg1 expressed macrophages on inflammatory milieu. We observed time-dependent increase expression, peaking at 7 d after photothrombotic stroke mice. Cellular mapping analysis revealed that was predominantly LysM-positive infiltrating macrophages. Using conditional knockout (cKO) mouse model, we examined Contrary presumed beneficial effects, cKO significantly improved skilled forelimb motor function Mechanistically, attenuated fibrotic scar formation, enhanced peri-infarct remyelination, increased synaptic density while reducing microglial elimination cortex. Gene expression fluorescence-activated single cell sorting (FACS)-sorted CD45 low microglia decreased transforming growth factor-β (TGF-β) signaling proinflammatory cytokine activity from animals. In vitro coculture experiments demonstrated modulates phagocytosis, providing evidence macrophage–microglia interaction. These findings present unique insights into central nervous system injury highlight an interaction between resident shaping Our identifies as potential therapeutic target modulating improving recovery.

Language: Английский

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Zinc accumulation aggravates cerebral ischemia/reperfusion injury by promoting inflammation

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: March 8, 2023

Intracellular zinc accumulation has been shown to be associated with neuronal death after cerebral ischemia. However, the mechanism of leading in ischemia/reperfusion (I/R) is still unclear. signals are required for production proinflammatory cytokines. The present study investigated whether intracellular accumulated aggravates I/R injury through inflammatory response, and inflammation-mediated apoptosis. Male Sprague-Dawley rats were treated vehicle or chelator TPEN 15 mg/kg before a 90-min middle artery occlusion (MCAO). expressions cytokines TNF-α, IL-6, NF-κB p65, inhibitory protein IκB-α, as well anti-inflammatory cytokine IL-10 assessed at 6 24 h reperfusion. Our results demonstrated that expression p65 increased reperfusion, while IκB-α decreased, suggesting ischemia triggers response. Furthermore, all colocalized neuron-specific nuclear (NeuN), ischemia-induced response occurs neurons. Moreover, TNF-α was also zinc-specific dyes Newport Green (NG), might inflammation following I/R. Chelating reversed ischemic rats. Besides, IL-6-positive cells TUNEL-positive penumbra MCAO indicating induce inflammation-associated Taken together, this demonstrates excessive activates brain caused by least partially due specific apoptosis induced inflammation, which may provide an important injury.

Language: Английский

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Intranasal Delivery of Curcumin Nanoparticles Improves Neuroinflammation and Neurological Deficits in Mice with Intracerebral Hemorrhage

Small Methods, Journal Year: 2024, Volume and Issue: unknown

Published: April 5, 2024

Abstract Intracerebral hemorrhage (ICH) represents one of the most severe subtypes stroke. Due to complexity brain injury mechanisms following ICH, there are currently no effective treatments significantly improve patient functional outcomes. Curcumin, as a potential therapeutic agent for is limited by its poor water solubility and oral bioavailability. In this study, mPEG‐PCL used encapsulate curcumin, forming curcumin nanoparticles, utilized intranasal administration route directly deliver nanoparticles from nasal cavity brain. By inhibiting pro‐inflammatory neuroinflammation microglia ICH in mice, reprogramming toward an anti‐inflammatory function, consequently reducing neuronal inflammatory death hematoma volume, approach improved blood‐brain barrier damage mice promoted recovery neurological function post‐stroke. This study offers promising strategy mediate neuroinflammatory microenvironments.

Language: Английский

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Sex differences in the effects of high fat diet on underlying neuropathology in a mouse model of VCID

Biology of Sex Differences, Journal Year: 2023, Volume and Issue: 14(1)

Published: May 19, 2023

Abstract Background Damage to the cerebral vasculature can lead vascular contributions cognitive impairment and dementia (VCID). A reduction in blood flow brain leads neuropathology, including neuroinflammation white matter lesions that are a hallmark of VCID. Mid-life metabolic disease (obesity, prediabetes, or diabetes) is risk factor for VCID which may be sex-dependent (female bias). Methods We compared effects mid-life between males females chronic hypoperfusion mouse model C57BL/6J mice were fed control high fat (HF) diet starting at ~ 8.5 months age. Three after initiation, sham unilateral carotid artery occlusion surgery (VCID model) was performed. later, underwent behavior testing brains collected assess pathology. Results have previously shown this model, HF causes greater wider array deficits males. Here, we report on sex differences underlying specifically changes several areas brain. White negatively impacted by females, with correlating less myelin markers only. High led an increase microglia activation but not females. Further, decrease proinflammatory cytokines pro-resolving mediator mRNA expression Conclusions The current study adds our understanding neuropathology presence common (obesity/prediabetes). This information crucial development effective, sex-specific therapeutic interventions

Language: Английский

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Neuroprotective effects of Jie-du-huo-xue decoction on microglia pyroptosis after cerebral ischemia and reperfusion——From the perspective of glial-vascular unit

Journal of Ethnopharmacology, Journal Year: 2023, Volume and Issue: 318, P. 116990 - 116990

Published: Aug. 1, 2023

Ischemic stroke poses a serious risk to public health and quality of life. Jie-Du-Huo-Xue decoction (JDHXD) is classical well-known Chinese formula for treatment, but the pharmacological mechanism still unclear.This study aims investigate underlying microglial pyroptosis polarization, as well potential efficacy JDHXD against cerebral ischemia-reperfusion injury (CIRI).Models CIRI were established by middle artery occlusion/reperfusion (MCAO/R) method in rats. In first stage, 36 SD rats randomly divided into sham group, I/R JDHXD-L group (5.36 g/kg/day), JDHXD-M (10.71 JDHXD-H (21.42 positive drug edaravone group. The effectiveness on was confirmed neurological function testing infarct measuring. best dose (JDXHD-M) subsequently chosen perform tests that followed. second Detection nerve damage using Nissl staining, proteins pyroptosis, Iba-1, NeuN expressions detected western blotting, M1/M2 phenotypic polarization immunofluorescence.In after CIRI, significantly reduced impairment infarction. addition, facilitated M1-to-M2 transition microglia order minimize neuroinflammation improve anti-inflammatory repair. JDXHD inhibited blocking cleavage caspase-1 P10 gasdermin D, hence reducing neuronal enhancing survival following reperfusion. Interestingly, also demonstrated protective effect glial-vascular unit (GVU).Our investigation exerted GVU-protective decreasing neuroinflammation-associated suppressing M1 activation, promoting M2 activation.

Language: Английский

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Novel HOCl-Responsive Theranostic Prodrug for the Early Diagnosis and Therapy of Ischemic Stroke

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 12, 2025

In this work, a hypochlorous acid (HOCl)-responsive prodrug MB-R for diagnosis and therapy of ischemic stroke (IS) was constructed using the near-infrared fluorophore methylene blue linked to riluzole by urea bond. exhibits good biocompatibility, fast response (<1 min), high selectivity toward HOCl. successfully utilized visualize HOCl levels, as well distribution in brains IS mice determine progression disease. Meanwhile, treatment with could reduce cerebral infarction volume improve motor function mice. Most importantly, be through antioxidant, anti-inflammatory, neuroprotective effects, further suggesting that potentially therapeutic agent IS. Thus, work paves way development intelligent theranostic early

Language: Английский

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LRRC8A in endothelial cells contributes to the aberrant blood-brain barrier integrity in ischaemic stroke

Stroke and Vascular Neurology, Journal Year: 2025, Volume and Issue: unknown, P. svn - 003675

Published: March 16, 2025

Background The increased permeability of the blood-brain barrier (BBB) is a critical contributor to high mortality following ischaemic stroke. However, mechanisms regulating BBB integrity remain poorly understood. Leucine-rich repeat-containing 8A (LRRC8A) chloride channel for cellular volume homeostasis and plays key role in neuronal injury during ischaemia. its impact on function currently unclear. Methods A transient middle cerebral artery occlusion model was established investigate LRRC8A integrity. Laser speckle contrast imaging used monitor cortical blood flow. Primary mouse human brain microvascular endothelial cells (m/hBMVECs) were subjected oxygen-glucose deprivation (OGD) re-oxygenation varying durations. Patch-clamp recordings performed measure volume-regulated currents. Immunostaining conducted evaluate protein expression. Cell evaluated with transwell assay. Results deletion ameliorates infarct area mitigates leakage. Ischaemia dramatically upregulates expression cells, concurrently downregulating tight junction proteins. OGD exposure augments VRCC current mediated by BMVECs. In contrast, inhibiting promotes ZO-1 VE-cadherin, thereby preserving cells. With-no-lysine kinase 1 (WNK1) inhibition contributes LRRC8A-induced damage post-ischaemic Eupatorin, newly identified inhibitor, exerts neuroprotective effects against Conclusions BMVECs pivotal modulating integrity, process regulated WNK1. As an Eupatorin holds potential stroke therapy.

Language: Английский

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Microglial Responses to MSC-EVs Treatment in Animal and Cellular Models of Ischemic Stroke: a Systematic Review with Meta-analysis

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

Language: Английский

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Intestinal Akkermansia muciniphila is Beneficial to Functional Recovery Following Ischemic Stroke

Journal of Neuroimmune Pharmacology, Journal Year: 2024, Volume and Issue: 19(1)

Published: Aug. 14, 2024

Language: Английский

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