Impact of Metabolic Syndrome on Neuroinflammation and the Blood–Brain Barrier

Dyken, Peter Van; Lacoste, Baptiste

doi:10.3389/fnins.2018.00930

Cited by 261 publications

(191 citation statements)

References 250 publications

(345 reference statements)

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“…FOXO1 regulates vascular endothelial growth factor A (VEGFA) expression and promotes angiogenesis in healing wounds (28). Under inflammatory conditions, VEGF increases vascular permeability (29), an effect mediated by cldn5 disruption (30). It will be interesting to further evaluate endothelial cell signaling in prospective studies.…”

Section: Discussionmentioning

confidence: 99%

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Dudek

Dion‐Albert

Lebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

242

177

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Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

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Section: Discussionmentioning

confidence: 99%

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Dudek

Dion‐Albert

Lebel

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

242

177

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“…One energetically favorable miRNA-146a and/or miRNA-155 mRNA target, both confirmed by bioinformatics and miRNA-mRNA-3'-UTR binding luciferase-reporter assay, is the 3'-untranslated region (3'-UTR) of complement factor H (CFH) mRNA resulting in, respectively, the down-regulation of CFH expression [26,27,48,87]. A down-regulated CFH is associated with the disruption of innate-immune signaling that supports inflammatory neurodegeneration and amyloidogenesis [17,34,36,45,55,75,[89][90][91]. Although CFH is easily detected in the brain parenchyma and neuronal cytoplasm it is also highly abundant in the blood serum of the human systemic circulation, as may be some other pathogenic blood-cell-based biomarkers that may include specific kinase mutations and other polymorphisms [17,45,55,68,91; see also https://www.sigmaaldrich.com/catalog/product/sigma/c5813?lang=en&region=US; ENSG000 00000971-CFH/ tissue; last accessed 4 July 2019].…”

Section: Up-regulated Micrornas (Mirnas) and Down-regulation Of Essenmentioning

confidence: 99%

“…Importantly, CFH has several structurally related proteins also encoded at the regulator of complement activation gene cluster at human chromosome 1q31.3 that lack relevant complement regulatory activity -these are known as CFH-related (CFHR) proteins [36,53,55]. The balance between the actions of CFH and the CFHR proteins: (i) determines the degree of complement activation and the innate-immune response; and (ii) regulates the neurophysiological roles of CFH and CFHR in CNS health and disease [36,75]. The functional contributions of CFH and CFHR-mediated signaling to the innate-immune response in inflammatory neurodegeneration are currently not completely understood [36,55,75].…”

Section: Up-regulated Micrornas (Mirnas) and Down-regulation Of Essenmentioning

confidence: 99%

“…The balance between the actions of CFH and the CFHR proteins: (i) determines the degree of complement activation and the innate-immune response; and (ii) regulates the neurophysiological roles of CFH and CFHR in CNS health and disease [36,75]. The functional contributions of CFH and CFHR-mediated signaling to the innate-immune response in inflammatory neurodegeneration are currently not completely understood [36,55,75].…”

Section: Up-regulated Micrornas (Mirnas) and Down-regulation Of Essenmentioning

confidence: 99%

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Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain

Alexandrov¹,

Zhai²,

Li³

et al. 2019

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Through the use of RNA sequencing, microRNA (miRNA) and messenger RNA (mRNA) microfluidic array analysis, LED Northern, Western and ELISA analysis and multiple bioinformatics algorithms we have discovered a novel route for pathogenic communication between the human gastrointestinal (GI)-tract microbiome and the brain. The evidence suggests that this pathogenic gut-brain circuit involves: (i) lipopolysaccharide (LPS) from the GI-tract resident enterotoxigenic Gram-negative bacteria Bacteroides fragilis (BF-LPS); (ii) LPS transit across the GI-tract barrier into the systemic circulation; (iii) transport of a highly pro-inflammatory systemic BF-LPS across the blood-brain barrier (BBB) into the brain-parenchyma and neuronal-cytoplasm; (iv) activation and signaling via the pro-inflammatory NF-kB (p50/p65) transcription-factor complex; (v) NF-kB-coupling and significant up-regulation of the inducible pro-inflammatory microRNA-146a (miRNA-146a) and microRNA-155 (miRNA-155); each containing multiple NF-kB DNA-binding and activation sites in their immediate promoters; and (vi) subsequent down-regulation of miRNA-146a-miRNA-155 regulated mRNA targets such as that encoding complement factor H (CFH), a soluble complement control glycoprotein and key repressor of the innate-immune response. Down-regulated CFH expression activates the complement-system, the major non-cellular component of the innate-immune system while propagating neuro-inflammation. Other GI-tract microbes and their highly complex pro-inflammatory exudates may contribute to this pathogenic GI-tract-brain pathway. We speculate that it may be significant that the first Gram-negative anaerobic bacterial species intensively studied as a potential contributor to the onset of Alzheimer's disease (AD), that being the bacillus Bacteroides fragilis appears to utilize damaged or leaky physiological barriers and an activated NF-kB (p50-p65)-pro-inflammatory miRNA-146a-miRNA-155 signaling circuit to convey microbiome-derived pathogenic signals into the brain.

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“…Moderate CNS involvement with ALL (CNS 2) in the setting of obesity may be due to technical difficulty during a diagnostic lumbar puncture (ie obtaining peripheral blood elements in the sample), the biologic gradient seen in our study (though not statistically significant due to the limited number of CNS positive cases) suggests this finding is real and not purely due to technique. Additionally, other studies have shown obesity can impact neuro-inflammation and the permeability of the blood brain barrier [44][45][46][47] suggesting a biological mechanism for ALL penetration into the CNS in patients who are obese.…”

Section: Discussionmentioning

confidence: 99%

Body mass index associated with childhood and adolescent high‐risk B‐cell acute lymphoblastic leukemia risk: A Children’s Oncology Group report

et al. 2020

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Background Obesity is a risk factor for many adulthood cancers, but its role in childhood, adolescent, and young adult (AYA) cancer is unknown. Childhood and AYA acute lymphoblastic leukemia (ALL) incidence and obesity prevalence have shown concurrent increases. We sought to identify whether obesity may be a risk factor for childhood and AYA ALL. Methods Characteristics from individuals with ALL, aged 2‐30 years, diagnosed 2004‐2017 and treated on Children's Oncology Group (COG) protocols with available pre‐treatment anthropometric data (N = 4726) were compared to National Health and Nutrition Examination Survey controls (COG AALL17D2). Body mass index (BMI) was defined using standard CDC definitions. Multivariate conditional logistic regression assessed associations between BMI and ALL with additional analyses stratified by sex and race/ethnicity. Results Among cases (72% high‐risk (HR) B‐ALL, 28% T‐ALL), 5% had underweight, 58% normal weight, 17% overweight, and 20% obesity. Underweight (OR 2.11, 95% CI 1.56‐2.85) and obesity (OR 1.32, 95% CI 1.15‐1.53) were associated with B‐ALL diagnosis. Specifically, obesity was associated with B‐ALL among males (OR 1.57, 95% CI 1.30‐1.91) and Hispanic children (OR 1.78, 95% CI 1.39‐2.29). Obesity was also associated with central nervous system (CNS) involvement. Conclusion Pre‐treatment obesity is associated with HR B‐ALL among males and Hispanics, as well as with CNS involvement, suggesting common physiology between obesity and leukemogenesis. An association between underweight and ALL was confirmed, likely due to cancer‐associated wasting. These results have important public health implications for obesity prevention and treatment in children and adolescents to reduce cancer risk.

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Impact of Metabolic Syndrome on Neuroinflammation and the Blood–Brain Barrier

Cited by 261 publications

References 250 publications

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression

Lipopolysaccharide-stimulated, NF-kB-, miRNA-146a- and miRNA-155-mediated molecular-genetic communication between the human gastrointestinal tract microbiome and the brain

Body mass index associated with childhood and adolescent high‐risk B‐cell acute lymphoblastic leukemia risk: A Children’s Oncology Group report

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