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25-Hydroxycholesterol attenuates tumor necrosis factor alpha-induced blood-brain barrier breakdown in vitro
Open accessAbstract
Intracellular cholesterol metabolism is regulated by the SREBP-2 and LXR signaling pathways. The effects of inflammation on these molecular mechanisms remain poorly studied, especially at the blood-brain barrier (BBB) level. Tumor necrosis factor α (TNFα) is a proinflammatory cytokine associated with BBB dysfunction. Therefore, the aim of our study was to investigate the effects of TNFα on BBB cholesterol metabolism, focusing on its underlying signaling pathways. Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types. TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion. In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased. In HBPs, only LDLR and ABCA1 expression is increased. TNFα treatment also induces 25-hydroxycholesterol (25-HC) production, a cholesterol metabolite involved in the immune response and intracellular cholesterol metabolism. 25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression. Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1-independent mechanism at the BBB, while it activates the SREBP-2 pathway. Treatment with 25-HC partially reversed the effect of TNFα on the LXR/SREBP-2 pathways. Our study provides novel perspectives for better understanding cerebrovascular signaling events linked to BBB dysfunction and cholesterol metabolism in neuroinflammatory diseases.
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Written from the paper’s full text.
TL;DR
In a human in vitro BBB model of CD34+-derived brain-like endothelial cells (hBLECs) and human brain pericytes (HBPs), TNFα increased permeability, degraded CLAUDIN-5 via late endosomes, and altered cholesterol metabolism. Pretreatment with 25-HC attenuated TNFα-induced BBB leakage and partially reversed TNFα effects on ABCA1, LDLR, and HMGCR, suggesting SREBP-2-dependent protection.
Key findings
- TNFα (1 and 10 ng/mL) induced inflammatory markers NLRP3, VCAM-1, and ICAM-1 in hBLECs and HBPs; BBB disruption began after 8 h, with increased sodium fluorescein permeability and decreased TEER (basal TEER 80.4 ± 6.8 Ω·cm²), and 10 ng/mL TNFα for 24 h was chosen for subsequent experiments.
- TNFα promoted CLAUDIN-5 relocalization to RAB7A-positive late endosomes (increased Pearson’s correlation at 24 h) and decreased CLDN5 protein at 48 h, alongside disturbed CLAUDIN-5, ZO-1, and VE-CADHERIN localization.
- TNFα downregulated ABCA1 in hBLECs but upregulated it in HBPs; upregulated LDLR in both cell types and HMGCR in hBLECs; and increased cholesterol efflux to APOA-I and HDL and reduced intracellular/total cholesterol in hBLECs, but not HBPs, despite ABCA1 downregulation.
- TNFα increased 25-HC in both cell types and in basolateral/apical supernatants, with basal 25-HC production in HBPs 7.5-fold greater than in hBLECs; 25-HC (10 μM) pretreatment attenuated TNFα-induced permeability, improved junction localization, restored hBLEC survival, promoted HBP proliferation, and partially reversed TNFα effects on ABCA1, LDLR, and HMGCR, while the SREBP-2 inhibitor PF-429242—but not LXR modulators—partially restored permeability.
Methods
- Human in vitro BBB model: CD34+-hematopoietic stem cell-derived endothelial cells were cocultured with HBPs on Transwell inserts; after 5 days, endothelial cells acquired BBB properties and were termed hBLECs. Treatments were in serum-free medium, with TNFα or IFNγ added to the basolateral compartment and 25-HC or inhibitors added 15 min before TNFα.
- Assays included sodium fluorescein permeability, TEER, WST-1/ATP/lactate/MTT viability and metabolic assays, immunofluorescence and confocal analysis, RT-qPCR, Western blotting, [³H]-cholesterol efflux to APOA-I or HDL, total cholesterol quantification, and LC-MS/MS for 25-HC.
- Statistics used GraphPad Prism; normality was assessed by Shapiro-Wilk or Kolmogorov-Smirnov tests, followed by Mann-Whitney/Kruskal-Wallis or Student’s t-test/one-way ANOVA, with significance set at p < 0.05, p < 0.01, and p < 0.001.
Limitations
- The paper does not include a formal limitations section; the text states that the molecular events leading to ABCA1 down- and upregulation in hBLECs and HBPs remain to be elucidated, whether another transporter mediates cholesterol efflux remains to be determined, CH25H and CYP7B1 protein changes were not confirmed, and 7α,25-DHC was not detected.
- Evident from the text: findings are from an in vitro human BBB model rather than in vivo; HBPs were isolated from a single patient who died from a heart attack, and CD34+ cells were from human umbilical cord blood, so donor variability and generalizability are not established.
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- Findingown data
TNFα treatment induces 25-HC production in the human in vitro BBB model.
“TNFα treatment also induces 25-hydroxycholesterol (25-HC) production, a cholesterol metabolite involved in the immune response and intracellular cholesterol metabolism.”
Quote in the paperSubstantial claim - Findingown data
In HBPs, TNFα increases ABCA1 expression.
“In HBPs, only LDLR and ABCA1 expression is increased.”
Quote in the paperNot a substantial claim - Findingown data
In hBLECs, TNFα increases LDLR expression.
“In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased.”
Quote in the paperSubstantial claim - Findingown data
TNFα decreases APOE secretion in the human in vitro BBB model.
“TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion.”
Quote in the paperSubstantial claim - Findingown data
In hBLECs, TNFα decreases ABCA1 expression.
“In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased.”
Quote in the paperSubstantial claim
- Findingown data
25-HC pretreatment attenuates TNFα-induced blood-brain barrier leakage in the human in vitro BBB model.
“25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression.”
- Also stated in: § 1. Introduction · plain
“At last, pretreatment with 25-HC, which inhibits the SREBP-2 pathway, attenuated the TNFα-induced BBB breakdown.”
Quote in the paperSubstantial claim - Also stated in: § 1. Introduction · plain
- Findingown data
In HBPs, TNFα increases LDLR expression.
“In HBPs, only LDLR and ABCA1 expression is increased.”
Quote in the paperNot a substantial claim - Findingown data
25-HC pretreatment partially alleviates the effect of TNFα on LDLR expression.
“25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression.”
Quote in the paperSubstantial claim - Findingown data
TNFα increases blood-brain barrier permeability in the human in vitro BBB model composed of hBLECs and HBPs.
“Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types.”
Quote in the paperSubstantial claim - Findingown data
TNFα promotes cholesterol release in the human in vitro BBB model.
“TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion.”
Quote in the paperSubstantial claim - Findingown data
In hBLECs, TNFα increases HMGCR expression.
“In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased.”
Quote in the paperSubstantial claim - Findingown data
TNFα decreases cholesterol accumulation in the human in vitro BBB model.
“TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion.”
Quote in the paperSubstantial claim - Findingown data
TNFα degrades the tight junction protein CLAUDIN-5 in the human in vitro BBB model.
“Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment partially alleviates the effect of TNFα on HMGCR expression.
“25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression.”
Quote in the paperSubstantial claim - Findingown data
TNFα activates stress signaling pathways in both hBLECs and HBPs.
“Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment partially alleviates the effect of TNFα on ABCA1 expression.
“25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression.”
Quote in the paperSubstantial claim - Findingown data
1 ng/mL TNFα has no effect on ABCA1 expression.
“However, 1 ng/mL TNFα, which had a mild effect on BBB permeability and did not induce hBLEC toxicity, had no effect on ABCA1 expression.”
Quote in the paperNot a substantial claim - Findingown data
25-HC pretreatment attenuates TNFα-induced BBB disruption after 24 h of treatment.
“As shown in Fig. 7A, the pretreatment with 25-HC attenuated TNFαinduced BBB disruption after 24 h of treatment”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment restored hBLEC survival after TNFα treatment.
“Finally, 25-HC pretreatment restored hBLEC survival after TNFα treatment (Fig. 7D)”
Quote in the paperSubstantial claim - Findingreasoning
In hBLECs, despite ABCA1 downregulation, cholesterol release is promoted.
“Despite ABCA1 downregulation in hBLECs, cholesterol release is promoted thus suggesting that this process is ABCA1-independent, and that it might be involved in the inflammatory response as recently suggested in other cell types (18).”
Quote in the paperSubstantial claim - Findingown data
TNFα downregulates LXRα expression in hBLECs.
“and TNFα downregulates LXRα expression in hBLECs”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment improves the cell border localization of CLAUDIN-5, ZO-1, and VE-CADHERIN.
“In addition, Fig. 7B confirms that pretreatment with 25-HC improved the cell border localization of CLAUDIN-5, ZO-1 and VE-CADHERIN”
Quote in the paperSubstantial claim - Findingown data
7α,25-DHC was not detected with or without TNFα treatment.
“Notably, we also assessed the 7α,25-DHC levels, but we were not able to detect this lipid with or without TNFα treatment.”
Quote in the paperNot a substantial claim - Findingown data
TNFα treatment induces a significant change in hBLEC morphology, highlighted by stronger F-ACTIN labelling.
“TNFα treatment induces a significant change in hBLEC morphology, as highlighted by F-ACTIN labelling that appears stronger.”
Quote in the paperNot a substantial claim - Findingown data
25-HC pretreatment partially reverses the TNFα-induced change in hBLEC morphology.
“This trend is partially reversed by 25-HC pretreatment (Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data
Basal 25-HC production in HBPs is 7.5-fold greater than in hBLECs.
“Again, differences in lipid metabolism between HBPs and hBLECs are underlined since basal 25-HC production in HBPs is 7.5-fold greater than that in hBLECs.”
Quote in the paperNot a substantial claim - Findingown data
CYP7B1 expression was not detected in hBLECs.
“CYP7B1 expression was not detected in hBLECs but was increased by TNFα in HBPs (Fig. 6B).”
Quote in the paperNot a substantial claim - Findingown data
10 ng/mL TNFα increased lactate production in hBLECs.
“and increased lactate production (Supplementary Fig. 2)”
Quote in the paperNot a substantial claim - Findingown data
TNFα treatment upregulates ICAM-1 in hBLECs at 4, 8, 24, and 48 h.
“The inflammasome molecule NOD-like receptor family, pyrin domaincontaining 3 (NLRP3, Fig. 1A), vascular cell adhesion molecule-1 (VCAM-1, Fig. 1B), and intercellular adhesion molecule 1 (ICAM-1, Fig. 1C) were significantly upregulated in hBLECs after 4, 8, 24 and 48 h of treatment with various concentrations of TNFα.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment decreases Pearson's correlation coefficient of CLDN5-RAB7A colocalization.
“that is further confirmed by a decrease of Pearson's correlation coefficient obtained by confocal analysis (Supplementary Fig. 6).”
Quote in the paperNot a substantial claim - Findingown data
CYP7B1 expression is increased by TNFα in HBPs.
“CYP7B1 expression was not detected in hBLECs but was increased by TNFα in HBPs (Fig. 6B).”
Quote in the paperNot a substantial claim - Findingown data
BBB disruption was more evident after 24 and 48 h, when 10 ng/mL TNFα further increased BBB permeability.
“BBB disruption was more evident after 24 and 48 h of treatment, when 10 ng/mL TNFα was able to further increase the BBB permeability.”
Quote in the paperSubstantial claim - Findingown data
25-HC promotes HBP viability.
“25-HC also alleviated the toxicological effects of TNFα on hBLECs (D) and promoted HBP viability (E).”
Quote in the paperSubstantial claim - Findingown data
TNFα treatment upregulates NLRP3 in hBLECs at 4, 8, 24, and 48 h.
“The inflammasome molecule NOD-like receptor family, pyrin domaincontaining 3 (NLRP3, Fig. 1A), vascular cell adhesion molecule-1 (VCAM-1, Fig. 1B), and intercellular adhesion molecule 1 (ICAM-1, Fig. 1C) were significantly upregulated in hBLECs after 4, 8, 24 and 48 h of treatment with various concentrations of TNFα.”
Quote in the paperSubstantial claim - Findingown data
TNFα treatment strongly upregulates CH25H mRNA in HBPs.
“TNFα treatment decreased CH25H mRNA (Fig. 6B) in hBLECs but strongly upregulated its expression in HBPs (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment (10 μM, 15 min) alleviates the increase in paracellular permeability induced by TNFα (10 ng/mL, 24 h) in the in vitro BBB model.
“25-HC alleviates the increase in paracellular permeability induced by TNFα (A).”
Quote in the paperSubstantial claim - Findingown data
Pretreatment of hBLECs with 25-HC decreases TNFα-induced colocalization of CLAUDIN-5 with RAB7A.
“Pretreatment of hBLECs with 25-HC decreased this colocalization.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment decreases CLAUDIN-5 localization with RAB7A-positive late endosomes.
“and decreased CLAUDIN-5 localization with RAB7A-positive late endosomes (Fig. 7C)”
Quote in the paperSubstantial claim - Findingown data
TNFα upregulates LDLR expression in hBLECs and HBPs.
“TNFα upregulated the expression of LDLR in hBLECs and HBPs (Fig. 4A and E)”
- Also stated in: § Contribution · plain
“In parallel, TNFα activates the SREBP-2 pathway, thus leading to upregulation of LDLR and HMGCR expression.”
Quote in the paperSubstantial claim - Also stated in: § Contribution · plain
- Findingown data
10 ng/mL TNFα reduces intracellular cholesterol content in hBLECs.
“and reduced the intracellular cholesterol content in hBLECs (Fig. 5C and D).”
Quote in the paperSubstantial claim - Findingown data
10 ng/mL TNFα downregulates ABCA1 mRNA and protein expression in hBLECs.
“Surprisingly, 10 ng/mL TNFα downregulated the mRNA and protein expression of ABCA1 in hBLECs, but upregulated ABCA1 expression in HBPs (Fig. 4A and B).”
Quote in the paperSubstantial claim - Findingown data
CLAUDIN-5 protein levels in hBLECs are decreased 48 h after TNFα treatment.
“Protein levels of CLAUDIN-5 were decreased 48 h after TNFα treatment.”
Quote in the paperSubstantial claim - Findingown data
There is a significant increase of Pearson's correlation of CLDN5-RAB7A colocalization at 24 h after TNFα treatment.
“We observed a significant increase of Pearson's correlation of CLDN5-RAB7A colocalization at 24 h after TNFα treatment (Fig. 2E)”
Quote in the paperSubstantial claim - Findingreasoning
ABCA1 expression is increased in HBPs after TNFα treatment.
“ABCA1 expression is increased in HBPs while it is decreased in hBLECs, likely via the LXRβ upregulation in HBPs and LXRα downregulation in hBLECs.”
Quote in the paperNot a substantial claim - Findingown data
ABCA1 expression is decreased in hBLECs after TNFα treatment.
“ABCA1 expression is increased in HBPs while it is decreased in hBLECs, likely via the LXRβ upregulation in HBPs and LXRα downregulation in hBLECs.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment promoted HBP proliferation.
“and promoted HBP proliferation, as showed in Fig. 7E.”
Quote in the paperNot a substantial claim - Findingown data
25-HC pretreatment inhibits the TNFα-induced ABCA1 downregulation.
“while it inhibited the TNFα-induced ABCA1 downregulation (Fig. 9).”
Quote in the paperSubstantial claim - Findingown data
No changes in cholesterol efflux were detected in HBPs treated with TNFα.
“No changes in cholesterol efflux were detected in HBPs treated with TNFα”
Quote in the paperSubstantial claim - Findingown data
TNFα treatment decreases CH25H mRNA in hBLECs.
“TNFα treatment decreased CH25H mRNA (Fig. 6B) in hBLECs but strongly upregulated its expression in HBPs (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
TNFα increases HMGCR expression only in hBLECs.
“and increased the expression of HMGCR only in hBLECs (Fig. 4A and E).”
Quote in the paperNot a substantial claim - Findingown data
TNFα-treated cells presented disabled junction proteins CLAUDIN-5, ZO-1, and VE-CADHERIN.
“The TNFα-induced BBB breakdown was further confirmed by immunofluorescence analysis, that revealed that TNFαtreated cells presented disabled junction proteins, such as CLAUDIN-5, ZO-1, and VE-CADHERIN (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
TNFα had no effect on HBP viability and ATP production at any tested concentration.
“Interestingly, TNFα had no effect on HBP viability and ATP production at any tested concentration”
Quote in the paperNot a substantial claim - Findingown data
TNFα increases BBB permeability in a human in vitro BBB model.
“Using a human BBB model, we demonstrated that TNFα increases BBB permeability by translocating CLAUDIN-5 in RAB7A-positive late endosomes, and by changing hBLEC morphology linked to a strong F-ACTIN remodeling.”
Quote in the paperSubstantial claim - Findingown data
TNFα treatment upregulates inflammatory markers in HBPs.
“Similar results were observed for HBPs (Fig. 1D), confirming that the inflammatory process is induced by TNFα in both cell types of the human BBB model.”
Quote in the paperSubstantial claim - Findingown data
No APOE protein secretion was detected on the apical side of the model.
“Interestingly, we were not able to detect any secretion of APOE protein on the apical side of the model (blood).”
Quote in the paperNot a substantial claim - Findingown data
T0901317 increased cholesterol efflux in HBPs.
“while T0901317 increased cholesterol efflux”
Quote in the paperNot a substantial claim - Findingown data
TNFα promotes 25-HC production.
“TNFα also promotes 25-HC production that in turn alleviates the TNFα effects on the BBB permeability and on the cholesterol metabolism.”
Quote in the paperSubstantial claim - Findingown data
TNFα upregulates HMGCR expression in hBLECs and HBPs.
“In parallel, TNFα activates the SREBP-2 pathway, thus leading to upregulation of LDLR and HMGCR expression.”
Quote in the paperSubstantial claim - Findingown data
TNFα treatment (10 ng/mL, 24 h) increases colocalization of CLAUDIN-5 with RAB7A in hBLECs.
“Calculation of Pearson's correlation coefficient from confocal pictures shows an increase of CLAUDIN-5 and RAB7A colocalization after 24 h of TNFα treatment.”
Quote in the paperSubstantial claim - Findingown data
LXRα is highly expressed in hBLECs and HBPs compared with LXRβ.
“LXRα is highly expressed in hBLECs and in HBPs when compared with LXRβ (Supplementary Fig. 3)”
Quote in the paperSubstantial claim - Findingown data
10 ng/mL TNFα decreases APOE in basolateral supernatants of the human BBB model.
“and this result was confirmed by analysis of cell supernatants from the basolateral compartment (brain) of the human BBB model (Fig. 4D).”
Quote in the paperNot a substantial claim - Findingown data
10 ng/mL TNFα increases cholesterol efflux to APOA-I and HDL only in hBLECs.
“As shown in Figs.5A and B, 10 ng/mL TNFα increased cholesterol efflux to both acceptors (APOA-1 and HDL) only in hBLECs”
Quote in the paperNot a substantial claim - Findingown data
10 ng/mL TNFα slightly decreased hBLEC viability.
“TNFα (10 ng/mL) slightly decreased hBLEC viability (Fig. 3A)”
Quote in the paperNot a substantial claim - Findingown data
T0901317 treatment (LXR activation) leads to cholesterol efflux.
“The results observed after T0901317 (10 μM) treatment confirmed that activation of the LXR signaling pathway leads to cholesterol efflux.”
Quote in the paperNot a substantial claim - Findingown data
25-HC pretreatment reduces the effects of TNFα on the protein expression of ABCA1, LDLR and HMGCR in hBLECs.
“Pretreatment of hBLECs with 25-HC reduces the effects of TNFα on the protein expression of ABCA1, LDLR and HMGCR.”
Quote in the paperSubstantial claim - Findingown data
10 ng/mL TNFα upregulates ABCA1 expression in HBPs.
“Surprisingly, 10 ng/mL TNFα downregulated the mRNA and protein expression of ABCA1 in hBLECs, but upregulated ABCA1 expression in HBPs (Fig. 4A and B).”
Quote in the paperNot a substantial claim - Findingown data
Increased cholesterol efflux was observed in both compartments of the human BBB model.
“Interestingly, increased cholesterol efflux was observed in both compartments of the human BBB model.”
Quote in the paperSubstantial claim - Findingown data
No cholesterol efflux is triggered in HBPs despite alterations in LDLR and ABCA1 expression.
“Despite alterations in LDLR and ABCA1 expression, no cholesterol efflux is triggered in HBPs.”
Quote in the paperNot a substantial claim - Findingown data
25-HC alleviates the toxicological effects of TNFα on hBLECs.
“25-HC also alleviated the toxicological effects of TNFα on hBLECs (D) and promoted HBP viability (E).”
Quote in the paperSubstantial claim - Findingown data
There is a significant decrease of CLDN5 protein level at 48 h after TNFα treatment.
“and a significant decrease of CLDN5 protein level at 48 h (Fig. 2F).”
Quote in the paperSubstantial claim - Findingown data
Protein levels of CH25H and CYP7B1 were not affected by TNFα.
“However, further immunoblot studies did not confirm these increases or decreases and suggested that the protein levels of CH25H and CYP7B1 were not affected by TNFα (Fig. 6C and D).”
Quote in the paperNot a substantial claim - Findingown data
10 ng/mL TNFα slightly decreased ATP content in hBLECs.
“TNFα (10 ng/mL) slightly decreased hBLEC viability (Fig. 3A) and ATP content (Fig. 3B)”
Quote in the paperNot a substantial claim - Findingown data
In hBLECs treated with 1 or 10 ng/mL TNFα for 24 h, loss of cell border cohesion was observed.
“Loss of cell border cohesion was shown by white arrows.”
Quote in the paperSubstantial claim - Findingown data
25-HC pretreatment partially abolishes the TNFα-induced overexpression of LDLR and HMGCR.
“In this regard, pretreatment with 25-HC partially abolished the TNFα-induced overexpression of LDLR and HMGCR”
Quote in the paperSubstantial claim - Findingown data
IFNγ upregulates 25-HC production in our BBB model.
“we first showed that IFNγ upregulates 25-HC production in our BBB model (Supplementary Fig. 5)”
Quote in the paperNot a substantial claim - Findingown data
25-HC alone does not upregulate ABCA1.
“Interestingly, we did not observe ABCA1 upregulation in the presence of 25-HC alone”
Quote in the paperSubstantial claim - Findingown data
10 ng/mL TNFα downregulates APOE mRNA in hBLECs at 24 h.
“RT-qPCR analysis of APOE mRNA showed downregulation 24 h after treatment with TNFα 10 ng/mL in hBLECs (Fig. 4A)”
Quote in the paperNot a substantial claim - Findingown data
TNFα upregulates LXRβ expression in HBPs.
“and upregulates LXRβ expression in HBPs (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
TNFα has no effect on protein expression of ABCG1, ABCG4, and ABCA7.
“Other ABC transporters (ABCG1, ABCG4, and ABCA7) known as cholesterol transporters were also investigated but TNFα had no effect on their protein expression (Supplementary Fig. 4).”
Quote in the paperNot a substantial claim - Findingown data
TNFα treatment upregulates VCAM-1 in hBLECs at 4, 8, 24, and 48 h.
“The inflammasome molecule NOD-like receptor family, pyrin domaincontaining 3 (NLRP3, Fig. 1A), vascular cell adhesion molecule-1 (VCAM-1, Fig. 1B), and intercellular adhesion molecule 1 (ICAM-1, Fig. 1C) were significantly upregulated in hBLECs after 4, 8, 24 and 48 h of treatment with various concentrations of TNFα.”
Quote in the paperSubstantial claim - Findingown data
25-HC release was increased in both basolateral and apical supernatants of the human BBB model.
“In addition, 25-HC release was increased in the two cell culture supernatants contained in the two compartments (basolateral and apical) of the human BBB model (Fig. 6G).”
Quote in the paperSubstantial claim - Interpretationown data
Treatment with 25-HC partially reverses the effect of TNFα on the LXR/SREBP-2 pathways.
“Treatment with 25-HC partially reversed the effect of TNFα on the LXR/SREBP-2 pathways.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα alters cholesterol metabolism at the hBLEC and HBP levels via activation of the SREBP-2 pathway.
“Herein, we demonstrated first that TNFα induces BBB disruption via CLAUDIN-5 degradation and alters cholesterol metabolism at the hBLEC and HBP levels via activation of the SREBP-2 pathway.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα increases blood-brain barrier permeability through degradation of CLAUDIN-5.
“Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα increases 25-HC bioavailability in the in vitro BBB model.
“Secondly, our data suggested that TNFα increases 25-HC bioavailability.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα favors cholesterol efflux via an LXR/ABCA1-independent mechanism at the blood-brain barrier.
“Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1independent mechanism at the BBB, while it activates the SREBP-2 pathway.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα activates the SREBP-2 pathway at the blood-brain barrier.
“Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1independent mechanism at the BBB, while it activates the SREBP-2 pathway.”
Quote in the paperSubstantial claim - Premisecitation
25-HC plays a key role in the regulation of inflammatory processes in the brain.
“For instance, recent findings have demonstrated that 25-hydroxycholestherol (25-HC) inhibits SREBP-2 function and plays a key role in the regulation of inflammatory processes in the brain (reviewed in (26)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
TNFα-mediated cholesterol efflux is not mediated by ABCA1.
“These results support the hypothesis suggesting that TNFα-mediated cholesterol efflux is not mediated by ABCA1.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 is the major cholesterol transporter involved in APOA-I and HDL efflux.
- Interpretationown data
HBPs are less sensitive to the deleterious effects of TNFα than are hBLECs.
“suggesting that HBPs are less sensitive to the deleterious effects of TNFα than are hBLECs.”
Quote in the paperNot a substantial claim - Premisecitation
ABCA1 inhibition does not decrease cholesterol efflux after TNFα treatment in red blood cells or solo-cultured HBPs.
“Recent studies reported the same observations in red blood cells (55) or in solocultured HBPs since ABCA1-inhibition was not able to decrease cholesterol efflux after TNFα treatment (18).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [55]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
TNFα-induced inflammation activates the SREBP-2 signaling pathway.
“Since LDLR and HMGCR are regulated by the SREBP-2 pathway, we may conclude that TNFα-induced inflammation activates this signaling pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
- Interpretationown data
25-HC has protective effects on the BBB under inflammatory conditions.
“which further supports the hypothesis that 25-HC has protective effects on the BBB under inflammatory conditions.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα treatment modulates the levels of proteins involved in cholesterol efflux, production, and uptake.
“Taken together, our results suggest that TNFα treatment modulates the levels of proteins involved in cholesterol efflux, production and uptake.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 expression is regulated by LXRα and LXRβ.
- Rests on an assumption: ABCA1 is the major cholesterol transporter involved in APOA-I and HDL efflux.
- Interpretationown data
TNFα strongly affects cellular cholesterol homeostasis in hBLECs and HBPs via different mechanisms.
“TNFα also strongly affects cellular cholesterol homeostasis in hBLECs and HBPs via different mechanisms.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 expression is regulated by LXRα and LXRβ.
- Rests on an assumption: ABCA1 is the major cholesterol transporter involved in APOA-I and HDL efflux.
- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
- Interpretationreasoning
The increase in cholesterol efflux observed in hBLECs after TNFα treatment is not mediated by the LXR/ABCA1 axis.
“Taken together, these results suggest that the increase in cholesterol efflux observed in hBLECs after TNFα treatment is not mediated by the LXR/ABCA1 axis.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 expression is regulated by LXRα and LXRβ.
- Rests on an assumption: ABCA1 is the major cholesterol transporter involved in APOA-I and HDL efflux.
- Interpretationown data
25-HC may have protective effects at the BBB after TNFα treatment.
“Taken together, our findings suggest that 25-HC may have protective effects at the BBB after TNFα treatment”
Quote in the paperSubstantial claim - Interpretationown data
TNFα promotes the SREBP-2 signaling pathway in hBLECs and HBPs.
“TNFα promotes the SREBP-2 signaling pathway in hBLECs and HBPs.”
Quote in the paperSubstantial claim - Interpretationown data
25-HC does not act via the canonical LXR signaling pathway in hBLECs and HBPs.
“thus suggesting that this oxysterol does not act via the canonical LXR signaling pathway as it is observed in other cell types.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 expression is regulated by LXRα and LXRβ.
- Interpretationown data
TNFα increases BBB permeability by changing hBLEC morphology linked to a strong F-ACTIN remodeling.
“Using a human BBB model, we demonstrated that TNFα increases BBB permeability by translocating CLAUDIN-5 in RAB7A-positive late endosomes, and by changing hBLEC morphology linked to a strong F-ACTIN remodeling.”
Quote in the paperSubstantial claim - Interpretationreasoning
The decrease in ABCA1 in hBLECs is likely via LXRα downregulation.
“ABCA1 expression is increased in HBPs while it is decreased in hBLECs, likely via the LXRβ upregulation in HBPs and LXRα downregulation in hBLECs.”
Quote in the paperSubstantial claim - Interpretationown data
The beneficial effect of 25-HC on TNFα-induced BBB breakdown is possibly mediated by SREBP-2 inhibition.
“We can therefore conclude that the beneficial effect of 25-HC on the TNFα-induced BBB breakdown increase is possibly mediated by SREBP-2 inhibition.”
Quote in the paperSubstantial claim - Premisecitation
In the EAE mouse model of MS, levels of Ch25h, 25-HC, and 7α,25-DHC are increased in the CNS, including at the level of endothelial cells composing the BBB.
“In a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model, the levels of Ch25h, 25-HC, and 7α,25-DHC are increased in the CNS (59,60), including at the level of the endothelial cells composing the BBB (61).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [59]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [60]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [61]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Cholesterol plays a major role in the response to inflammation triggered by TNFα via the SREBP-2 pathway in both cell types.
“Taken together, these findings support a major role for cholesterol in the response to inflammation triggered by TNFα via the SREBP-2 pathway in both cell types.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
- Interpretationreasoning
The colocalization of CLAUDIN-5 with RAB7A likely leads to CLAUDIN-5 degradation.
“suggesting that it will likely lead to CLAUDIN-5 degradation.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα increases BBB permeability by translocating CLAUDIN-5 in RAB7A-positive late endosomes.
“Using a human BBB model, we demonstrated that TNFα increases BBB permeability by translocating CLAUDIN-5 in RAB7A-positive late endosomes, and by changing hBLEC morphology linked to a strong F-ACTIN remodeling.”
Quote in the paperSubstantial claim - Interpretationown data
TNFα triggers a different cellular response in HBPs than in hBLECs.
“suggesting that TNFα triggers a different cellular response in HBPs than in hBLECs.”
Quote in the paperSubstantial claim - Interpretationcitation
TNFα dose-dependently increases BBB permeability by modulating hBLEC tight junctions.
“TNFα dosedependently increases BBB permeability by modulating hBLEC tight junctions, as recently suggested (34,52).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [52]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
25-HC alleviates the effects of TNFα by inhibiting the SREBP-2 pathway.
“In turn, this oxysterol alleviates the effects of TNFα by inhibiting the SREBP-2 pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
- Premisecitation
When intracellular cholesterol content is high, a constant outflow of cholesterol ensures an increase of this lipid in ER.
“When the intracellular cholesterol content is high, a constant outflow of cholesterol ensures an increase of this lipid in ER (64).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
The increase in ABCA1 in HBPs is likely via LXRβ upregulation.
“ABCA1 expression is increased in HBPs while it is decreased in hBLECs, likely via the LXRβ upregulation in HBPs and LXRα downregulation in hBLECs.”
Quote in the paperNot a substantial claim - Interpretationreasoning
The cholesterol release process in hBLECs is ABCA1-independent.
“Despite ABCA1 downregulation in hBLECs, cholesterol release is promoted thus suggesting that this process is ABCA1-independent, and that it might be involved in the inflammatory response as recently suggested in other cell types (18).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- It may state two separate claims as one. 29
- The quote only partly states this claim. 1
- Probably not a substantial claim. 26
It may state two separate claims as one.
Findingown dataTNFα treatment disturbs cell border presence and increases cytosolic presence of junction proteins, particularly CLAUDIN-5.
“Cell border presence of these junction proteins is disturbed (white arrows) whereas cytosolic presence is increased, thus suggesting location changes of these proteins, particularly CLAUDIN-5 that is an essential component for BBB integrity (47).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth TNFα and IFNγ increased 25-HC production in both cell types.
“Fig. 6E and F show that both TNFα and IFNγ increased 25-HC production in both cell types.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data10 ng/mL TNFα decreases total cholesterol concentration in hBLECs but not in HBPs.
“Fig. 5E and F confirm that treatment of cells with 10 ng/mL of TNFα decreases the total cholesterol concentration in hBLECs, but not in HBPs.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataOnly pretreatment with 25-HC and with SREBP-2 inhibitor partially restored BBB permeability, with no significant difference between these conditions and the control.
“As shown in Fig. 8, only pretreatment with 25-HC and with SREBP-2 inhibitor partially restored the BBB permeability since there was no significant difference between these 2 conditions and the control condition.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data1 ng/mL TNFα had no effect on hBLEC viability, ATP content, or lactate production.
“while 1 ng/mL TNFα had no effect.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTNFα treatment promotes localization of CLAUDIN-5 in RAB7A-positive late endosomes, but not in endoplasmic reticulum labeled with HSP90B1, in hBLECs.
“TNFα treatment promoted the localization of CLAUDIN-5 in RAB7A-positive late endosomes, but not in endoplasmic reticulum labeled with HSP90B1.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAfter TNFα treatment, CLAUDIN-5 signal colocalizes with RAB7A but not with HSP90B1.
“We then adapted our immunofluorescence protocol to focus on intracellular CLAUDIN-5 localization after TNFα treatment and observed that CLAUDIN-5 signal superposes with RAB7A but not with HSP90B1 (Fig. 2D).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown data1 ng/mL TNFα induced BBB breakdown after 24 and 48 h, but to a lesser extent than 10 ng/mL TNFα.
“In addition, even 1 ng/mL TNFα induced BBB breakdown after 24 and 48 h, but to a lesser extent than 10 ng/mL TNFα.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data25-HC pretreatment did not alleviate NLRP3, VCAM-1, or COX-2 expression.
“Despite the beneficial effect observed on BBB permeability, 25-HC pretreatment did not alleviate NRLP3, VCAM-1 or COX-2 expression (Supplementary Fig. 8).”
Quote in the paperNot a substantial claimIt may state two separate claims as one. The quote only partly states this claim.
Findingown dataTNFα-induced BBB disruption starts after 8 h of treatment, indicated by increased NaFluo permeability and decreased TEER.
“the TNFα-induced BBB disruption started after 8 h of treatment, as highlighted by a marked increase of the permeability to sodium fluorescein (NaFluo)”
- Also stated in: § 3.1. TNFα triggers inflammation in cells of the human blood-brain barrier (BBB) and promotes BBB opening · plain
“and a decrease of the trans-endothelial electrical resistance (TEER) (Fig. 2B).”
Quote in the paperSubstantial claim- Also stated in: § 3.1. TNFα triggers inflammation in cells of the human blood-brain barrier (BBB) and promotes BBB opening · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll experiments were carried out in accordance with the approved protocol.
“All experiments were carried out in accordance with the approved protocol.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHMGCR and LDLR are regulated by the SREBP-2 pathway.
“On the other hand, the rate-limiting enzyme of cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and the low-density lipoprotein receptor (LDLR), which is responsible for the lipoprotein uptake, are both regulated by the sterol response element-binding protein 2 (SREBP-2) pathway (20)(21)(22)(23).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (20)(21)(22)(23)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Study design and conductcitationAfter 5 days of coculture, CD34+-ECs acquire the major BBB properties observed in vivo and reproduce a suitable model for investigating BBB permeability and physiology.
“After 5 days of coculture, CD34 + -ECs acquire the major BBB properties observed in vivo and reproduce a suitable model to for investigating BBB permeability and physiology (39,40).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Study design and conductnone givenTEER measurements were performed on triplicate inserts of two independent differentiations.
“TEER measurements were performed on triplicate inserts of two independent differentiations.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe collection of human umbilical cord blood required that infants' parents signed consent forms in compliance with French legislation.
“The collection of human umbilical cord blood requires that infants' parents signed consent forms in compliance with French legislation.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe protocol was approved by the French Ministry of Higher Education and Research (CODECOH, Number DC2011-1321).
“The protocol was approved by the French Ministry of Higher Education and Research (CODECOH, Number DC2011-1321).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataPearson's correlation coefficients were calculated using 10 fields per condition in 3 independent experiments.
“Pearson's correlation coefficient were then calculated using 10 fields per condition in 3 independent experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenHBPs and CD34+-hematopoietic stem cells were regularly checked for mycoplasma contamination, and STR analysis confirmed the absence of cross-contamination.
“HBPs and CD34 + -hematopoietic stem cells were regularly checked for mycoplasma contamination, and short tandem repeat (STR) analysis confirmed the absence of cross-contamination.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductcitationHBPs were deeply characterized in previous studies.
“HBPs were also deeply characterized in our previous studies (18,38,41).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisereasoningThe balance between LXR and SREBP-2 activation plays a key role in the regulation of cholesterol metabolism in the brain.
“In this way, the balance between LXR and SREBP-2 activation plays a key role on the regulation of cholesterol metabolism in the brain.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationABCA1 is the major cholesterol transporter involved in cholesterol release to apolipoproteins at the blood-brain barrier.
“Several studies have demonstrated that ABCA1 is the major cholesterol transporter involved in cholesterol release to apolipoproteins at the BBB and that its expression is regulated by the liver X receptor (LXR) pathway (17)(18)(19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (17)(18)(19)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationTNFα is a proinflammatory cytokine with well-described involvement in chronic neurological disorders and blood-brain barrier dysfunction.
“Tumor necrosis factor α (TNFα) a proinflammatory cytokine with well-described involvement in chronic neurological disorders and BBB dysfunction (33)(34)(35), was used to induce an inflammatory response in the in vitro BBB model.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (33)(34)(35)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenWritten informed consent was obtained from the family of the participant before enrollment in the study.
“For the CD34 + -hematopoietic stem cells, written informed consent was obtained from the family of the participant before enrollment in the study.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
PremisecitationABCA1 expression at the blood-brain barrier is regulated by the LXR pathway.
“Several studies have demonstrated that ABCA1 is the major cholesterol transporter involved in cholesterol release to apolipoproteins at the BBB and that its expression is regulated by the liver X receptor (LXR) pathway (17)(18)(19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (17)(18)(19)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenThe study protocol for human tissue was approved by the ethics committee of the Medical Faculty (IRB#: H18-033-6), University of Yamaguchi Graduate School, and was conducted in accordance with the Declaration of Helsinki.
“The study protocol for human tissue was approved by the ethics committee of the Medical Faculty (IRB#: H18-033-6), University of Yamaguchi Graduate School, and was conducted in accordance with the Declaration of Helsinki, as amended in Somerset West in 1996.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenHuman cells were handled in the laboratory under agreement number L2-1235.
“According to French legislation, human cells were handled in the laboratory under agreement number L2-1235.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation25-HC inhibits SREBP-2 function.
“For instance, recent findings have demonstrated that 25-hydroxycholestherol (25-HC) inhibits SREBP-2 function and plays a key role in the regulation of inflammatory processes in the brain (reviewed in (26)).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe specificity and efficiency of all target gene primers were evaluated before performing qPCR.
“The specificity and efficiency of all the target genes primers were evaluated before performing qPCR.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationCH25H is present in ER and leads to conversion of cholesterol into 25-HC.
“Since CH25H is present in ER, it leads to the conversion of cholesterol into 25-HC (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataThe external calibration curve for 25-HC was redone every 20 samples and showed linearity from 1 nM to 500 nM with a retention time of 3.8 min.
“External calibration curve was redone every 20 samples and shown linearity from 1 nM to 500 nM with a retention time at 3.8 min for 25-HC.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe in vitro BBB model had a basal TEER of 80.4 ± 6.8 Ω.cm2.
“The basal TEER was 80.4 ± 6.8 Ω.cm 2 .”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Premisecitation25-HC production leads to SREBP-2 trapping in the ER, which abolishes LDLR and HMGCR transcription and decreases cholesterol synthesis and uptake.
“Then, this oxysterol production leads to SREBP-2 trapping in the ER, which abolishes LDLR and HMGCR transcription and decreases cholesterol synthesis and uptake (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataTNFα upregulates 25-HC levels despite no measurable variations in CH25H and CYP7B1 expression.
“These data strongly suggest that despite no measurable variations in CH25H and CYP7B1 expression, the levels of 25-HC are upregulated by TNFα.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataTNFα disrupts the tight junctions of the hBLEC monolayer and promotes the translocation of CLAUDIN-5 to late endosomes to be subsequently degraded by the lysosomal system.
“Taken together, these results suggest that TNFα disrupts the tight junctions of the hBLEC monolayer and promotes the translocation of CLAUDIN-5 to the late endosomes to be subsequently degraded by the lysosomal system.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataCLAUDIN-5 is relocalized from the cell border to late endosomes and subsequently degraded, explaining the loss of permeability after TNFα treatment.
“Taken together, these results suggest that CLAUDIN-5 is relocalized from the cell border to late endosomes and subsequently degraded, thus explaining the loss of permeability observed after TNFα treatment.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationIn multiple sclerosis patients, BBB breakdown is reported and 25-HC levels are altered in CSF and plasma.
“In multiple sclerosis (MS) patients, a demyelinating disease, BBB breakdown is reported, and 25-HC levels are altered in CSF and in plasma (27,28).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation25-HC is a cholesterol metabolite mainly produced during inflammatory or infectious situations and contributes to immune response, CNS disorders, atherosclerosis, macular degeneration, and cancer development.
“In particular, 25-hydroxycholesterol (25-HC) is a cholesterol metabolite that is mainly produced during inflammatory or infectious situations and that in turn contributes to the immune response, CNS disorders, atherosclerosis, macular degeneration, and cancer development (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data25-HC essentially acts via the SREBP-2 pathway and not the LXR pathway in hBLECs and HBPs.
“These data suggest that 25-HC essentially acts via the SREBP-2 pathway and not the LXR pathway in hBLECs and HBPs.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
Probably not a substantial claim.
PremisecitationRAB7A-positive late endosomes fuse with lysosomes.
“It is well- described that RAB7A-positive late endosomes will then fuse with lysosomes (48)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataInflammation modulates 25-HC production, and this is the first time oxysterol production has been directly observed in BBB human cells.
“These results confirm that inflammation modulates 25-HC production, as already reported in other neural cells (59), but to our knowledge, this is the first time that oxysterol production has been directly observed in BBB human cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [59]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Premisenone givenCholesterol is converted to 25-HC by cholesterol 25 hydroxylase (CH25H).
“Cholesterol is converted to 25-HC by cholesterol 25 hydroxylase (CH25H) (Fig. 6A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisenone given25-HC can be converted by CYP7B1 to 7α,25-dihydroxycholesterol (7α,25-DHC), an agonist of EBI2 that elicits a strong inflammatory response.
“Afterwards, 25-HC can be subsequently converted by the enzyme CYP7B1 to 7α,25dihydroxycholesterol (7α,25-DHC), an agonist of Epstein-Barr receptor 2 (EBI2), which elicits a strong inflammatory response.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Premisecitation25-HC is a potent LXR agonist and inhibits the SREBP-2 pathway by sequestering SREBP proteins into the endoplasmic reticulum.
“Indeed, several studies have demonstrated that 25-HC is a potent LXR agonist and inhibits the SREBP-2 pathway by sequestering SREBP proteins into the endoplasmic reticulum (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data25-HC attenuates TNFα-induced LXR downregulation and SREBP-2 activation.
“In combination, these results suggest that 25-HC attenuates TNFα-induced LXR downregulation and SREBP-2 activation.”
Quote in the paperSubstantial claim- Rests on an assumption: ABCA1 expression is regulated by LXRα and LXRβ.
- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
Probably not a substantial claim.
PremisecitationPF-429242 prevents SREBP-2 cleavage by inhibiting the site-1-protease.
“PF-429242 (that prevents SREBP-2 cleavage by inhibiting the site-1-protease (51))”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [51]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataTNFα affects BBB integrity and cholesterol metabolism via activation of the SREBP-2 pathway and promotes 25-HC production.
“Our results suggest that TNFα affects BBB integrity and cholesterol metabolism via activation of the SREBP-2 pathway and promotes 25-HC production.”
Quote in the paperSubstantial claim- Rests on an assumption: LDLR and HMGCR expression is regulated by SREBP-2.
It may state two separate claims as one.
Interpretationown dataTNFα quickly triggers an inflammatory response in HBPs and hBLECs via activation of NLRP3, followed by upregulation of ICAM-1 and VCAM-1.
“Our results suggest that, when added to the basolateral compartment of the human BBB model, TNFα quickly triggers an inflammatory response in HBPs and hBLECs via the activation of the inflammasome protein NLRP3, followed by the upregulation of ICAM-1 and VCAM-1, adhesion molecules that play a key role in immune cell infiltration.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may be too vague to check against evidence.
InterpretationreasoningThe findings provide new perspectives for the development of therapeutic approaches to counteract vascular dysfunctions in neuroinflammatory contexts.
“and provides new perspectives for the development of therapeutic approaches to counteract vascular dysfunctions in neuroinflammatory contexts.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCH25H is an interferon γ stimulated gene.
“Once CH25H, which is responsible for 25-HC production, is known to be an interferon γ stimulated gene (50)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [50]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
The interactions between TNFα, SREBP-2, the LXR/ABCA1 axis and 25-HC remain to be clarified, especially at the level of endothelial cells and pericytes of the blood-brain barrier.
“However, the interactions between TNFα, SREBP-2, the LXR/ABCA1 axis and 25-HC remain to be clarified, especially at the level of endothelial cells and pericytes of the BBB.”
The paper relies on this without support.
ABCA1 expression is regulated by LXRα and LXRβ.
“Because ABCA1 expression is regulated by LXRα and LXRβ, we measured the mRNA expression of these nuclear receptors after TNFα treatment.”
The paper relies on this without support.
ABCA1 is the major cholesterol transporter involved in APOA-I and HDL efflux.
“since ABCA1, the major cholesterol transporter involved in APOA-I and HDL efflux, was downregulated in hBLECs after TNFα treatment (Fig. 4A and B).”
The paper relies on this without support.
LDLR and HMGCR expression is regulated by SREBP-2.
“Since LDLR and HMGCR are regulated by the SREBP-2 pathway, we may conclude that TNFα-induced inflammation activates this signaling pathway.”
The paper relies on this without support.
T0901317 is a potent agonist of the LXR pathway.
“T0901317 (10 μM), a potent agonist of the LXR pathway, was used as a positive control.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Cholesterol-efflux incubation is reported as both 4 and 8 hours
MajorThe methods specify a 4-hour incubation with the lipid acceptors after treatment, but the Fig. 5 legend says cholesterol efflux was determined over 8 hours.
“After 24 h of treatment, the cells were rinsed once with ECGMV2 + 0.1 % BSA and incubated for 4 h with ECGMV2 + 0.1 % BSA containing 50 μg/mL of high-density lipoproteins (HDL) or 20 μg/mL of apolipoprotein A-I (APOA-I).”
“The efflux of cholesterol radiolabeled with the lipid acceptors APOA-I (A) and HDL (B) was determined for 8 h after 24 h of TNFα or T0901317 treatment.”
HMGCR upregulation in pericytes is reported inconsistently
MinorOne results passage says TNFα significantly upregulated HMGCR in both cell types; an earlier passage says HMGCR increased only in hBLECs.
“Given we have observed a significant upregulation of LDLR and HMGCR in HBPs and hBLECs after TNFα treatment, we hypothesize that TNFα is a potent activator of the SREBP-2 pathway.”
“TNFα upregulated the expression of LDLR in hBLECs and HBPs (Fig. 4A and E) and increased the expression of HMGCR only in hBLECs (Fig. 4A and E).”
Fig. 7 calls the human BBB model mice
MinorThe Fig. 7 legend describes mice being pretreated, whereas the paper identifies the experimental BBB model as an in vitro model made from human cells.
“In vitro BBB model mice were pretreated with 25-HC (10 μM) for 15 min and then treated with TNFα (10 ng/mL) for 24 h.”
“Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed”
Citations
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Structure and function of the blood–brain barrier
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Maxwell, K. F., Bhattacharya, S., Bodziak, M. L., Jakimovski, D., Hagemeier, J., Browne, R. W., Weinstock‐Guttman, B., Zivadinov, R., & Ramanathan, M. K. (2019) · Journal of Lipid Research · doi:10.1194/jlr.m089664 · Cited by 45
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Breaking the Barrier: The Role of Proinflammatory Cytokines in BBB Dysfunction
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Metadata
- Authors
- Loiola, R. A., Nguyen, C., Dib, S., Saint-Pol, J., Dehouck, L., Sevin, E., Naudot, M., Landry, C., Pahnke, J., Pot, C., & Gosselet, F.
- Affiliations
- Université d'Artois (FR)
- Centre National de la Recherche Scientifique (FR)
- Archéologie et Archéométrie (FR)
- Oslo University Hospital (NO)
- Centre Hospitalier Universitaire Vaudois (CH)
- Corresponding author
- Gosselet, Fabien
- ORCID
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 1870
- Issue
- 8
- Pages
- 167479
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W4401800495
- Cited by
- 20
- References
- 65
- Citations by year
- 2026: 9 · 2025: 11
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion, cc-by)
- PubMed (publishedVersion)
- SERVAL (Université de Lausanne) (publishedVersion, cc-by)
- HAL (submittedVersion, cc-by)
- IRIS (submittedVersion, cc-by)
- NORA - Norwegian Open Research Archives (submittedVersion, other-oa)
- Funders
- Ministerstvo Školství, Mládeže a Tělovýchovy (8F21002, RTD/2020/26, ES RTD/2020/26)
- Region Hauts-de-France
- German Research Foundation (263024513)
- Österreichische Forschungsförderungsgesellschaft (882717)
- Agence Nationale de la Recherche (20-JPW2-0002-04, ANR-21-CE14-0002, ANR-20-JPW2-0002-04, -21-CE14-0002)
- Conseil Régional Hauts-de-France
- European Regional Development Fund
- EU Joint Programme – Neurodegenerative Disease Research
- Stockholm Resilience Centre, Stockholm University (2020-02905)
- Swiss National Science Foundation (310030-192738)
- Bundesministerium für Bildung und Forschung (01ED2106)
- European Environment Agency
- Norges Forskningsråd (327571, 295910)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- 25-hydroxycholesterol, TNF-α, blood-brain barrier permeability, cholesterol metabolism, ABCA1, LDL receptor, HMGCR, claudin-5, tight junctions, brain pericytes, brain endothelial cells, neuroinflammation, cholesterol efflux
- MeSH terms
- Liver X Receptors, Apolipoproteins E, Blood-Brain Barrier, Cells, Cultured, Cholesterol, Humans, Hydroxycholesterols, Hydroxymethylglutaryl CoA Reductases, Receptors, LDL, Tumor Necrosis Factor-alpha, Signal Transduction, Pericytes, Endothelial Cells, Sterol Regulatory Element Binding Protein 2, ATP Binding Cassette Transporter 1
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