Microglia–blood vessel interactions: a double-edged sword in brain pathologies

Stanković, Nevenka Dudvarski; Teodorczyk, Marcin; Ploen, Robert; Zipp, Frauke; Schmidt, Mirko H. H.

doi:10.1007/s00401-015-1524-y

Cited by 245 publications

(155 citation statements)

References 186 publications

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“…Acquired and non-acquired disease states such as stroke, Alzheimer’s disease and others are associated with abnormal vascular function 19,20 . While extensive literature exists on stroke and its vascular effects/defects, there are scant reports related to traumatic brain injury (TBI).…”

Section: Discussionmentioning

confidence: 99%

Traumatic brain injury results in acute rarefication of the vascular network

Obenaus

Orantes

et al. 2017

Sci Rep

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The role of the cerebrovascular network and its acute response to TBI is poorly defined and emerging evidence suggests that cerebrovascular reactivity is altered. We explored how cortical vessels are physically altered following TBI using a newly developed technique, vessel painting. We tested our hypothesis that a focal moderate TBI results in global decrements to structural aspects of the vasculature. Rats (naïve, sham-operated, TBI) underwent a moderate controlled cortical impact. Animals underwent vessel painting perfusion to label the entire cortex at 1 day post TBI followed by whole brain axial and coronal images using a wide-field fluorescence microscope. Cortical vessel network characteristics were analyzed for classical angiographic features (junctions, lengths) wherein we observed significant global (both hemispheres) reductions in vessel junctions and vessel lengths of 33% and 22%, respectively. Biological complexity can be quantified using fractal geometric features where we observed that fractal measures were also reduced significantly by 33%, 16% and 13% for kurtosis, peak value frequency and skewness, respectively. Acutely after TBI there is a reduction in vascular network and vascular complexity that are exacerbated at the lesion site and provide structural evidence for the bilateral hemodynamic alterations that have been reported in patients after TBI.

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Section: Discussionmentioning

confidence: 99%

Traumatic brain injury results in acute rarefication of the vascular network

Obenaus

Orantes

et al. 2017

Sci Rep

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“…The central nervous system (CNS) has been considered an immunologically privileged site since it is distinctly separated from the peripheral immune system by the blood-brain barrier (BBB) [36]. However, it has emerged that immune B and T cells can infiltrate into the CNS from the periphery and mediate protracted but specific immune responses.…”

Section: Inflammationmentioning

confidence: 99%

Resilience and Vulnerability to Pain and Inflammation in the Hippocampus

Vasić

Schmidt

2017

IJMS

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Increasing evidence demonstrates the importance of hippocampal neurogenesis, a fundamental mechanism of neuroplasticity associated with cognition and emotion, in correlation to neurodegenerative and psychiatric disorders. Neuropsychiatric disorders are often a result of chronic stress or pain followed by inflammation; all these conditions manifest cognitive deficits and impairments in neurogenesis. However, while some individuals are more susceptible to stress, others are able to adapt to new environments via mechanisms of resilience. In light of this emerging field and based on extensive research, the role of neurogenesis is summarized and presented as a potentially powerful therapeutic tool.

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“…We therefore continued our studies to further understand the progression of this chronic, debilitating disease, by correlating cytokine, protein and neurotrophic factor concentrations and localizations, together with immune cell numbers and a loss of vascular integrity. This focus was partly due to recent research into vascular integrity and blood vessel function during chronic inflammation [23][24][25]. Using fluorescent tags and deconvolution imaging we examined vascular content, vessel integrity and vessel types in images of LPS treated rat olfactory bulbs and concluded that, by and large, vessels are overall intact but with 'suspect' areas.…”

Section: Introductionmentioning

confidence: 99%

Changes in Vascular and Immune Cell Content of an LPS Treated Rat Olfactory Bulb PD Model, Measured by Fluorescence Deconvolution Microscopy

Bick¹,

Poindexter²,

Doursout³

2017

J Cytokine Biol

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Objective: We have previously shown changes in protein, immune cell, nitric oxide a neurotrophic factor content and distribution in the olfactory bulb of an endotoxin-treated rat model, as all these factors have been shown to be involved in neurodegeneration. We expanded our studies by fluorescently imaging smooth muscle actin and endothelial nitric oxide synthase (eNOS), both markers of blood vessels, to investigate loss of vasculature content, as well as imaging locations and quantities of immune cells. The work was performed to shed further light on associations between vessel integrity and immune cell initiated endothelial disruption. Our goal was to demonstrate that cytokine production, NOS induction and immune cell increases, are likely part of the process that leads to a loss of olfaction and dopaminergic signaling and includes vascular perturbations.Methods: Rats were sacrificed following lipopolysaccharide (LPS) treatment. Olfactory bulbs were harvested, sectioned from top to bottom to include the tract and sensory neurons, and probed for markers of inflammation. Inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), eNOS, interleukin-1 beta (IL-1β), TNF-α, interleukin-6, glial cell derived neurotrophic factor (GDNF) and circulating nitric oxide (NO) were imaged together with tagged macrophages, T-cells, B-cells and neutrophils.Results: Serum NO levels indicated that an inflammatory episode had occurred, being significantly higher in treated animals, with tissue levels of NOS elevated for an extended period of time. Immune cell clusters were seen in a number of areas and the localization of NOS isomers suggests that they have divergent roles in neurodegeneration. For instance, eNOS was associated with blood vessels, iNOS with glial and matrix cells and nNOS with glial cells and neurons. T and B-cell numbers showed a sustained increase; neutrophil numbers rapidly increased then returned to baseline levels; macrophage numbers increased and remained high; LAMP positive cell numbers (NK-cells) increased and remained high; GDNF content increased; IL-6, TNF-α and IL-1β levels all rapidly increased, before dropping to untreated levels, while circulating, NO levels increased dramatically. Of interest, the images of vascular content, immune cell content, eNOS and smooth muscle actin, allowed us to show detrimental interactions between cells, factors and vessels. Our data show that the majority of the vessels were intact, though sections of interest were 'extracted' to reveal possible leaky areas. Specific sites of IL-6 positive lymphocyte clustering were noted around vessels, suggesting that interactions are occurring that lead to disruptions of blood vessel tunicae, allowing the internalization of circulating cells and subsequent cytokine-initiated endothelial cell death. Conclusion:Our findings suggest that protective GDNF and eNOS, which maintains vascular tone, are possibly synthesized too late to combat cytokine initiated neuron damage, glial activation and chronic loss of va...

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Microglia–blood vessel interactions: a double-edged sword in brain pathologies

Cited by 245 publications

References 186 publications

Traumatic brain injury results in acute rarefication of the vascular network

Traumatic brain injury results in acute rarefication of the vascular network

Resilience and Vulnerability to Pain and Inflammation in the Hippocampus

Changes in Vascular and Immune Cell Content of an LPS Treated Rat Olfactory Bulb PD Model, Measured by Fluorescence Deconvolution Microscopy

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