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Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.

ABSTRACT: Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

SUBMITTER: Haruwaka K

PROVIDER: S-EPMC6925219 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.

Haruwaka Koichiro K Ikegami Ako A Tachibana Yoshihisa Y Ohno Nobuhiko N Konishi Hiroyuki H Hashimoto Akari A Matsumoto Mami M Kato Daisuke D Ono Riho R Kiyama Hiroshi H Moorhouse Andrew J AJ Nabekura Junichi J Wake Hiroaki H

Nature communications 20191220 1

Microglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood-brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physi ...[more]

PMID: 31862977

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Project description:BackgroundNeuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.MethodsTo investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 μg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue.ResultsIn the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task.ConclusionsThese results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.

Project description:BACKGROUND:Ischemic stroke is a main cause of mortality. Blood-brain barrier (BBB) breakdown appears to play a critical role in inflammation in patients with ischemic stroke and acceleration of brain injury. The BBB has a protective function and is composed of endothelial cells, pericytes, and astrocytes. In ischemic stroke treatments, regulation of vascular endothelial growth factor (VEGF)-A and vascular endothelial growth factor receptor (VEGFR)-2 is a crucial target despite adverse effects. Our previous study found that loss of C-type lectin family 14 member A (CLEC14A) activated VEGF-A/VEGFR-2 signaling in developmental and tumoral angiogenesis. Here, we evaluate the effects of BBB impairment caused by CLEC14A deficiency in ischemia-reperfusion injury. METHODS:In vitro fluorescein isothiocyanate (FITC)-dextran permeability, transendothelial electrical resistance (TEER) assay, and immunostaining were used to evaluate endothelial integrity. BBB permeability was assessed using Evans blue dye and FITC-dextran injection in Clec14a-/- (CLEC14A-KO) mice and wild-type mice. Middle cerebral artery occlusion surgery and behavioral assessments were performed to evaluate the neurologic damage. The change of tight junctional proteins, adhesion molecules, pro-inflammatory cytokines, and microglial were confirmed by immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction of brain samples. RESULTS:In endothelial cells, knockdown of CLEC14A increased FITC-dextran permeability and decreased transendothelial electrical resistance; the severity of this effect increased with VEGF treatment. Immunofluorescence staining revealed that tight junctional proteins were attenuated in the CLEC14A knockdown endothelial cells. Consistent with the in vitro results, CLEC14A-KO mice that were injected with Evans blue dye had cerebral vascular leakage at postnatal day 8; wild-type mice had no leakage. We used a middle cerebral artery occlusion model and found that CLEC14A-KO mice had severe infarcted brain and neurological deficits with upregulated VEGFR-2 expression. FITC-dextran leakage was present in CLEC14A-KO mice after ischemia-reperfusion, and the numbers of tight junctional molecules were significantly decreased. Loss of CLEC14A increased the pro-inflammatory response through adhesion molecule expression, and glial cells were activated. CONCLUSIONS:These results suggest that activation of VEGFR-2 in CLEC14A-KO mice aggravates ischemic stroke by exacerbating cerebral vascular leakage and increasing neuronal inflammation after ischemia-reperfusion injury.

Project description:BackgroundThe blood-brain barrier (BBB) is a semipermeable interface that prevents the non-selective transport into the central nervous system. It controls the delivery of macromolecules fueling the brain metabolism and the immunological surveillance. The BBB permeability is locally regulated depending on the physiological requirements, maintaining the tissue homeostasis and influencing pathological conditions. Given its relevance in vertebrate CNS, it is surprising that little is known about the BBB in Amphibians, some of which are capable of adult CNS regeneration.ResultsThe BBB size threshold of the anuran Xenopus laevis (African clawed toad), as well as two urodele species, Ambystoma mexicanum (axolotl) and Pleurodeles waltl (Iberian ribbed newt), was evaluated under physiological conditions through the use of synthetic tracers. We detected important differences between the analyzed species. Xenopus exhibited a BBB with characteristics more similar to those observed in mammals, whereas the BBB of axolotl was found to be permeable to the 1 kDa tracer. The permeability of the 1 kDa tracer measured in Pleurodeles showed values in between axolotl and Xenopus vesseks. We confirmed that these differences are species-specific and not related to metamorphosis. In line with these results, the tight junction protein Claudin-5 was absent in axolotl, intermediate in Pleurodeles and showed full-coverage in Xenopus vessels. Interestingly, electron microscopy analysis and the retention pattern of the larger tracers (3 and 70 kDa) demonstrated that axolotl endothelial cells exhibit higher rates of macropinocytosis, a non-regulated type of transcellular transport.ConclusionsOur study demonstrated that, under physiological conditions, the blood-brain barrier exhibited species-specific variations, including permeability threshold, blood vessel coverage, and macropinocytosis rate. Future studies are needed to test whether the higher permeability observed in salamanders could have metabolic and immunological consequences contributing to their remarkable regenerative capacity.

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Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.

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Dual microglia effects on blood brain barrier permeability induced by systemic inflammation.

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