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Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

ABSTRACT: Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the ventricles of the brain that secretes cerebrospinal fluid (CSF), forms a blood-CSF barrier, and responds to disease conditions by recruiting immune cells and maintaining an immune microenvironment in the brain. Despite these critical roles, the exact structural and functional changes to the ChP over post-stroke time remain to be elucidated. We induced ischemic stroke in C57BL/6J mice via transient middle cerebral artery occlusion which led to reduction of cerebral blood flow and infarct stroke. At 1-7 days post-stroke, we detected time-dependent increase in the ChP blood-CSF barrier permeability to albumin, tight-junction damage, and dynamic changes of SPAK-NKCC1 protein complex, a key ion transport regulatory system for CSF production and clearance. A transient loss of SPAK protein complex but increased phosphorylation of the SPAK-NKCC1 complex was observed in both lateral ventricle ChPs. Most interestingly, stroke also triggered elevation of proinflammatory Lcn2 mRNA and its protein as well as infiltration of anti-inflammatory myeloid cells in ChP at day 5 post-stroke. These findings demonstrate that ischemic strokes cause significant damage to the ChP blood-CSF barrier, contributing to neuroinflammation in the subacute stage.

SUBMITTER: Chen Y

PROVIDER: S-EPMC10725199 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

Chen Yang Y Lin Lin L Bhuiyan Mohammad Iqbal H MIH He Kai K Jha Roshani R Song Shanshan S Fiesler Victoria M VM Begum Gulnaz G Yin Yan Y Sun Dandan D

Frontiers in cellular neuroscience 20231201

Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the ventricles of the brain that secretes cerebrospinal fluid (CSF), forms a blood-CSF barrier, and responds to disease conditions by recruiting immune cells and maintaining an immune microenvironment in the brain. Despite these critical roles, the exact structural and functional changes to the ChP over post-stroke time remain to be ...[more]

PMID: 38107410

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Project description:BackgroundThe choroid plexus (CP) has been recently implicated in the pathogenesis of the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). Lupus patients demonstrate increased serum and cerebrospinal fluid (CSF) concentrations of interleukin-6 (IL-6), which can disrupt vital blood-CSF barrier (B-CSFB) functions performed by the CP. However, difficulty accessing this tissue has largely precluded dynamic imaging or evaluation of CP barrier function in vivo.MethodsIn this study, explant CP spheroids which replicate the functional and structural properties of the B-CSFB were generated from 12 + week old female MRL/lpr (IL-6 wildtype; IL-6 WT) lupus mice, IL-6 knockout (IL-6 KO) MRL/lpr mice, and congenic control MRL/mpj mice. CP spheroids derived from IL-6 WT MRL/lpr mice were found to synthesize and secrete IL-6, similar to the CP in vivo, whereas the IL-6 KO spheroids did not produce IL-6. Accumulation of different fluorescent tracers within the central CSF-like fluid vacuole of spheroids, modeling brain ventricles, was measured to probe transcellular permeability, paracellular diffusion, and clearance functions of the CP.ResultsAs shown by blocking the IL-6 receptor in IL-6 WT spheroids or comparing them to IL-6 KO spheroids, IL-6 signaling decreased spheroid clearance of methotrexate, a chemotherapeutic drug employed in the therapy of lupus, and lucifer yellow. This suppression occurred without altering CP epithelial morphology and ultrastructure. Methotrexate and lucifer yellow efflux can occur through ATP-binding cassette (ABC) transporters, including BCRP and MRP1. Cytoplasmic accumulation of the ABC-specific dye fluorescein diacetate was also increased by IL-6. Pharmacologic inhibition of either BCRP or MRP1 in IL-6 KO spheroids was sufficient to recreate the clearance deficits observed in IL-6 WT spheroids. Moreover, CP expression of BCRP was significantly lower in IL-6 WT mice.ConclusionsIn this study, we establish, validate, and apply a CP spheroid model to the study of B-CSFB function in lupus. Our results show that IL-6, a key cytokine increased in NPSLE, can potentially suppress the CP-specific function and expression of BCRP and MRP1. Therefore, IL-6 could affect the CSF clearance of inflammatory substrates (e.g., leukotrienes), the accumulation of which would incite neurotoxicity and promote progression of NPSLE.

Project description:BackgroundAdropin is a peptide encoded by the energy homeostasis-associated gene (Enho) that is highly expressed in the brain. Aging and stroke are associated with reduced adropin levels in the brain and plasma. We showed that treatment with synthetic adropin provides long-lasting neuroprotection in permanent ischemic stroke. However, it is unknown whether the protective effects of adropin are observed in aged animals following cerebral ischemia/reperfusion. We hypothesized that adropin provides neuroprotection in aged mice subjected to transient middle cerebral artery occlusion.MethodsAged (18-24 months old) male mice were subjected to 30 minutes of middle cerebral artery occlusion followed by 48 hours or 14 days of reperfusion. Sensorimotor (weight grip test and open field) and cognitive tests (Y-maze and novel object recognition) were performed at defined time points. Infarct volume was quantified by 2,3,5-triphenyltetrazolium chloride staining at 48 hours or Cresyl violet staining at 14 days post-middle cerebral artery occlusion. Blood-brain barrier damage, tight junction proteins, and MMP-9 (matrix metalloproteinase-9) were assessed 48 hours after middle cerebral artery occlusion by ELISA and Western blots.ResultsGenetic deletion of Enho significantly increased infarct volume and worsened neurological function, whereas overexpression of adropin dramatically reduced stroke volume compared to wild-type controls. Postischemic treatment with synthetic adropin peptide given at the onset of reperfusion markedly reduced infarct volume, brain edema, and significantly improved locomotor function and muscular strength at 48 hours. Delayed adropin treatment (4 hours after the stroke onset) reduced body weight loss, infarct volume, and muscular strength dysfunction, and improved long-term cognitive function. Postischemic adropin treatment significantly reduced blood-brain barrier damage. This effect was associated with reduced MMP-9 and preservation of tight junction proteins by adropin treatment.ConclusionsThese data unveil a promising neuroprotective role of adropin in the aged brain after transient ischemic stroke via reducing neurovascular damage. These findings suggest that poststroke adropin therapy is a potential strategy to minimize brain injury and improve functional recovery in ischemic stroke patients.

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Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

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Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

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