scholarly journals TAK1 in brain endothelial cells mediates fever and lethargy

2011 ◽  
Vol 208 (13) ◽  
pp. 2615-2623 ◽  
Author(s):  
Dirk A. Ridder ◽  
Ming-Fei Lang ◽  
Sergei Salinin ◽  
Jan-Peter Röderer ◽  
Marcel Struss ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickness Behavior ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Endogenous Pyrogen ◽  
Inflammatory Stimuli ◽  
Cox 2 ◽  
Fever Response ◽  
The Brain ◽  
Pituitary Adrenal Axis

Systemic inflammation affects the brain, resulting in fever, anorexia, lethargy, and activation of the hypothalamus–pituitary–adrenal axis. How peripheral inflammatory signals reach the brain is still a matter of debate. One possibility is that, in response to inflammatory stimuli, brain endothelial cells in proximity to the thermoregulatory centers produce cyclooxygenase 2 (COX-2) and release prostaglandin E2, causing fever and sickness behavior. We show that expression of the MAP kinase kinase kinase TAK1 in brain endothelial cells is needed for interleukin 1β (IL-1β)–induced COX-2 production. Exploiting the selective expression of the thyroxine transporter Slco1c1 in brain endothelial cells, we generated a mouse line allowing inducible deletion of Tak1 specifically in brain endothelium. Mice lacking the Tak1 gene in brain endothelial cells showed a blunted fever response and reduced lethargy upon intravenous injection of the endogenous pyrogen IL-1β. In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior.

Abstract W P238: Selective Deletion of Pi3-kinase Gamma in the Brain Inhibits Tissue Plasminogen Activator-induced Brain Hemorrhage

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Rong Jin ◽  
Xiaolei Zhu ◽  
Cuiping Wang ◽  
Anil Nanda ◽  
D Neil Granger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Brain Hemorrhage ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Chimeric Mice ◽  
Ischemic Brain ◽  
Tissue Plasminogen ◽  
The Brain

Background: PI3-kinase gamma (PI3Kγ), a key modulator in inflammation, is involved in many inflammatory diseases. We recently reported that PI3Kγ deficiency protects the brain from ischemic injury in PI3Kγ-/- mice by reducing blood-brain barrier damage and tissue infarction through inhibition of NF-kB-dependent inflammation, mainly involved in reduced MMP-9 activity in ischemic brain endothelium, microglia activation, and neutrophil infiltration into the ischemic brain. Meanwhile, we reported that ischemic brain endothelium, activated microglia, and infiltrating neutrophils represent the major cellular sources of PI3Kγ expressed in the brain within 24 h after cerebral ischemia. Brain hemorrhage is a serious complication of recombinant tissue plasminogen activator (tPA) therapy for ischemic stroke. In this study, we further investigated potential involvement of PI3Kγ, in particular the expression of PI3Kγ in the brain, in tPA-induced brain hemorrhage after ischemic stroke. Methods and Results: Focal ischemic stroke was induced by transient middle cerebral artery occlusion and reperfusion. PI3Kγ deficiency in PI3Kγ-/- mice not only reduced tissue infarction but also almost completely blocked brain hemorrhage induced by delayed tPA treatment at 6 hours after stroke. Bone marrow chimeras reveal that chimeric mice lacking PI3Kγ in the brain (WT BM →KO) blocked the delayed tPA-induced brain hemorrhage effectively as found in PI3Kγ-/- mice while chimeric mice lacking PI3Kγ expressed in leukocytes (KO BM →WT) had minimal effect on the tPA-induced brain hemorrhage. These effects could be attributed to a profound inhibition of MMP-9 activity in ischemic brain endothelium found in both PI3Kγ-/- mice and (WT BM →KO) chimeric mice but not in (KO BM →WT) chimeric mice, as determined by double IHC staining of MMP-9 in brain endothelial cells and by zymographic analysis of MMP-9 activity using microvessels isolated from the brain. Conclusion: Our findings suggest that PI3Kγ in the brain may play a predominant role in delayed tPA-induced brain hemorrhage after ischemic stroke. Our future study will define the role of PI3Kγ derived from brain endothelial cells versus microglia by generation of tissue/cell-specific knockout mice using the Cre-loxP system.

Attenuated fever in pregnant rats is associated with blunted syntheses of brain cyclooxygenase-2 and PGE2

2002 ◽  
Vol 283 (6) ◽  
pp. R1346-R1353 ◽  
Author(s):  
Kyoko Imai-Matsumura ◽  
Kiyoshi Matsumura ◽  
Akira Terao ◽  
Yasuyoshi Watanabe
Keyword(s):  
Endothelial Cells ◽  
Cyclooxygenase 2 ◽  
Female Rats ◽  
Brain Endothelial Cells ◽  
Term Pregnancy ◽  
Pregnant Rats ◽  
Near Term ◽  
Fever Response ◽  
Colonic Temperature ◽  
The Brain

Attenuation of fever occurs in pregnant animals. This study examined a hypothesis that brain production of PGE2, the final mediator of fever, is suppressed in pregnant animals. Near-term pregnant rats and age-matched nonpregnant female rats were injected with lipopolysaccharide (100 μg/kg) intraperitoneally. Four hours later, colonic temperature was measured, their cerebrospinal fluid (CSF) was sampled for PGE2 assay, and their brains were processed for immunohistochemistry of cyclooxygenase-2, an enzyme involved in PGE2 biosynthesis. In the pregnant rats, lipopolysaccharide injection resulted in significantly smaller elevations in both colonic temperature and CSF-PGE2 level than in nonpregnant rats. In the pregnant rats, lipopolysaccharide-induced cyclooxygenase-2 expression was blunted in terms of the number of positive cells. There was a significant correlation between PGE2 level in CSF and the number of cyclooxygenase-2-positive endothelial cells. These results suggest that suppressed PGE2 production in the brain is one cause for the attenuated fever response at near-term pregnancy and that this suppressed PGE2 production is due to the suppressed induction of cyclooxygenase-2 in brain endothelial cells.

scholarly journals The Role of BAR Proteins and the Glycocalyx in Brain Endothelium Transcytosis

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2685
Author(s):  
Diana M. Leite ◽  
Diana Matias ◽  
Giuseppe Battaglia
Keyword(s):  
Endothelial Cells ◽  
Small Molecules ◽  
The Other ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Transcellular Transport ◽  
Molecular Transporters ◽  
Membrane Bound ◽  
The Brain

Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled from one side to the other through membrane-bound carriers formed by endocytosis on one side, trafficked to the other side and released by exocytosis. Such a process is collectively known as transcytosis. The brain endothelium is recognised to possess an intricate vesicular endosomal network that mediates the transcellular transport of cargos from blood-to-brain and brain-to-blood. However, mounting evidence suggests that brain endothelial cells (BECs) employ a more direct route via tubular carriers for a fast and efficient transport from the blood to the brain. Here, we compile the mechanism of transcytosis in BECs, in which we highlight intracellular trafficking mediated by tubulation, and emphasise the possible role in transcytosis of the Bin/Amphiphysin/Rvs (BAR) proteins and glycocalyx (GC)—a layer of sugars covering BECs, in transcytosis. Both BAR proteins and the GC are intrinsically associated with cell membranes and involved in the modulation and shaping of these membranes. Hence, we aim to summarise the machinery involved in transcytosis in BECs and highlight an uncovered role of BAR proteins and the GC at the brain endothelium.

scholarly journals Targeting nanoparticles to the brain by exploiting the blood–brain barrier impermeability to selectively label the brain endothelium

2020 ◽  
Vol 117 (32) ◽  
pp. 19141-19150 ◽  
Author(s):  
Daniel Gonzalez-Carter ◽  
Xueying Liu ◽  
Theofilus A. Tockary ◽  
Anjaneyulu Dirisala ◽  
Kazuko Toh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Target Proteins ◽  
Blood Brain ◽  
Brain Microvasculature ◽  
The Brain

Current strategies to direct therapy-loaded nanoparticles to the brain rely on functionalizing nanoparticles with ligands which bind target proteins associated with the blood–brain barrier (BBB). However, such strategies have significant brain-specificity limitations, as target proteins are not exclusively expressed at the brain microvasculature. Therefore, novel strategies which exploit alternative characteristics of the BBB are required to overcome nonspecific nanoparticle targeting to the periphery, thereby increasing drug efficacy and reducing detrimental peripheral side effects. Here, we present a simple, yet counterintuitive, brain-targeting strategy which exploits the higher impermeability of the BBB to selectively label the brain endothelium. This is achieved by harnessing the lower endocytic rate of brain endothelial cells (a key feature of the high BBB impermeability) to promote selective retention of free, unconjugated protein-binding ligands on the surface of brain endothelial cells compared to peripheral endothelial cells. Nanoparticles capable of efficiently binding to the displayed ligands (i.e., labeled endothelium) are consequently targeted specifically to the brain microvasculature with minimal “off-target” accumulation in peripheral organs. This approach therefore revolutionizes brain-targeting strategies by implementing a two-step targeting method which exploits the physiology of the BBB to generate the required brain specificity for nanoparticle delivery, paving the way to overcome targeting limitations and achieve clinical translation of neurological therapies. In addition, this work demonstrates that protein targets for brain delivery may be identified based not on differential tissue expression, but on differential endocytic rates between the brain and periphery.

scholarly journals Cryptococcus neoformans Promotes Its Transmigration into the Central Nervous System by Inducing Molecular and Cellular Changes in Brain Endothelial Cells

2013 ◽  
Vol 81 (9) ◽  
pp. 3139-3147 ◽  
Author(s):  
Kiem Vu ◽  
Richard A. Eigenheer ◽  
Brett S. Phinney ◽  
Angie Gelli
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Human Brain ◽  
Cryptococcus Neoformans ◽  
Brain Endothelial Cells ◽  
Brain Endothelium ◽  
Content Type ◽  
The Central Nervous System ◽  
The Brain

ABSTRACTCryptococcusspp. cause fungal meningitis, a life-threatening infection that occurs predominately in immunocompromised individuals. In order forCryptococcus neoformansto invade the central nervous system (CNS), it must first penetrate the brain endothelium, also known as the blood-brain barrier (BBB). Despite the importance of the interrelation betweenC. neoformansand the brain endothelium in establishing CNS infection, very little is known about this microenvironment. Here we sought to resolve the cellular and molecular basis that defines the fungal-BBB interface during cryptococcal attachment to, and internalization by, the human brain endothelium. In order to accomplish this by a systems-wide approach, the proteomic profile of human brain endothelial cells challenged withC. neoformanswas resolved using a label-free differential quantitative mass spectrometry method known as spectral counting (SC). Here, we demonstrate that as brain endothelial cells associate with, and internalize, cryptococci, they upregulate the expression of several proteins involved with cytoskeleton, metabolism, signaling, and inflammation, suggesting that they are actively signaling and undergoing cytoskeleton remodeling via annexin A2, S100A10, transgelin, and myosin. Transmission electronic microscopy (TEM) analysis demonstrates dramatic structural changes in nuclei, mitochondria, the endoplasmic reticulum (ER), and the plasma membrane that are indicative of cell stress and cell damage. The translocation of HMGB1, a marker of cell injury, the downregulation of proteins that function in transcription, energy production, protein processing, and the upregulation of cyclophilin A further support the notion thatC. neoformanselicits changes in brain endothelial cells that facilitate the migration of cryptococci across the BBB and ultimately induce endothelial cell necrosis.

scholarly journals Two peptides targeting endothelial receptors are internalized into murine brain endothelial cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0249686
Author(s):  
Diána Hudecz ◽  
Sara Björk Sigurdardóttir ◽  
Sarah Christine Christensen ◽  
Casper Hempel ◽  
Andrew J. Urquhart ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transferrin Receptor ◽  
Vesicular Transport ◽  
Brain Diseases ◽  
Brain Endothelial Cells ◽  
Binding Studies ◽  
Wide Range ◽  
Murine Brain ◽  
The Brain

The blood-brain barrier (BBB) is one of the main obstacles for therapies targeting brain diseases. Most macromolecules fail to pass the tight BBB, formed by brain endothelial cells interlinked by tight junctions. A wide range of small, lipid-soluble molecules can enter the brain parenchyma via diffusion, whereas macromolecules have to transcytose via vesicular transport. Vesicular transport can thus be utilized as a strategy to deliver brain therapies. By conjugating BBB targeting antibodies and peptides to therapeutic molecules or nanoparticles, it is possible to increase uptake into the brain. Previously, the synthetic peptide GYR and a peptide derived from melanotransferrin (MTfp) have been suggested as candidates for mediating transcytosis in brain endothelial cells (BECs). Here we study uptake, intracellular trafficking, and translocation of these two peptides in BECs. The peptides were synthesized, and binding studies to purified endocytic receptors were performed using surface plasmon resonance. Furthermore, the peptides were conjugated to a fluorophore allowing for live-cell imaging studies of their uptake into murine brain endothelial cells. Both peptides bound to low-density lipoprotein receptor-related protein 1 (LRP-1) and the human transferrin receptor, while lower affinity was observed against the murine transferrin receptor. The MTfp showed a higher binding affinity to all receptors when compared to the GYR peptide. The peptides were internalized by the bEnd.3 mouse endothelial cells within 30 min of incubation and frequently co-localized with endo-lysosomal vesicles. Moreover, our in vitro Transwell translocation experiments confirmed that GYR was able to cross the murine barrier and indicated the successful translocation of MTfp. Thus, despite binding to endocytic receptors with different affinities, both peptides are able to transcytose across the murine BECs.

scholarly journals Endogenous THBD (Thrombomodulin) Mediates Angiogenesis in the Ischemic Brain—Brief Report

2020 ◽  
Vol 40 (12) ◽  
pp. 2837-2844 ◽  
Author(s):  
Jan Wenzel ◽  
Dimitrios Spyropoulos ◽  
Julian Christopher Assmann ◽  
Mahtab Ahmad Khan ◽  
Ines Stölting ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Soluble Form ◽  
Stroke Outcome ◽  
Brain Endothelial Cells ◽  
Ischemic Brain ◽  
Infarct Area ◽  
The Brain

Objective: THBD (thrombomodulin) is part of the anticoagulant protein C-system that acts at the endothelium and is involved in anti-inflammatory and barrier-stabilizing processes. A recombinant soluble form of THBD was shown to have protective effects in different organs, but how the endogenous THBD is regulated during ischemia, particularly in the brain is not known to date. The aim of this study was to investigate the role of THBD, especially in brain endothelial cells, during ischemic stroke. Approach and Results: To induce ischemic brain damage, we occluded the middle cerebral artery of mice. We found an increased endothelial expression of Thbd in the peri-infarct area, whereas in the core of the ischemic tissue Thbd expression was decreased compared with the contralateral side. We generated a novel Cre/loxP-based mouse line that allows for the inducible deletion of Thbd specifically in brain endothelial cells, which worsened stroke outcome 48 hours after middle cerebral artery occlusion. Unexpectedly, we found no signs of increased coagulation, thrombosis, or inflammation in the brain but decreased vessel diameters and impaired angiogenesis in the peri-infarct area that led to a reduced overall vessel length 1 week after stroke induction. Conclusions: Endogenous THBD acts as a protective factor in the brain during ischemic stroke and enhances vessel diameter and proliferation. These previously unknown properties of THBD could offer new opportunities to affect vessel function after ischemia and thereby improve stroke outcome.

scholarly journals Interaction between Endothelial Protein C Receptor and Intercellular Adhesion Molecule 1 to Mediate Binding of Plasmodium falciparum -Infected Erythrocytes to Endothelial Cells

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Marion Avril ◽  
Maria Bernabeu ◽  
Maxwell Benjamin ◽  
Andrew Jay Brazier ◽  
Joseph D. Smith
Keyword(s):  
Endothelial Cells ◽  
Cerebral Malaria ◽  
Intercellular Adhesion Molecule ◽  
Brain Endothelial Cells ◽  
Endothelial Protein C Receptor ◽  
Intercellular Adhesion Molecule 1 ◽  
Cd36 Expression ◽  
Tnf Α ◽  
Group A ◽  
The Brain

ABSTRACT Intercellular adhesion molecule 1 (ICAM-1) and the endothelial protein C receptor (EPCR) are candidate receptors for the deadly complication cerebral malaria. However, it remains unclear if Plasmodium falciparum parasites with dual binding specificity are involved in cytoadhesion or different parasite subpopulations bind in brain microvessels. Here, we investigated this issue by studying different subtypes of ICAM-1-binding parasite lines. We show that two parasite lines expressing domain cassette 13 (DC13) of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family have dual binding specificity for EPCR and ICAM-1 and further mapped ICAM-1 binding to the first DBLβ domain following the PfEMP1 head structure in both proteins. As PfEMP1 head structures have diverged between group A (EPCR binders) and groups B and C (CD36 binders), we also investigated how ICAM-1-binding parasites with different coreceptor binding traits influence P. falciparum -infected erythrocyte binding to endothelial cells. Whereas levels of binding to tumor necrosis factor alpha (TNF-α)-stimulated endothelial cells from the lung and brain by all ICAM-1-binding parasite lines increased, group A (EPCR and ICAM-1) was less dependent than group B (CD36 and ICAM-1) on ICAM-1 upregulation. Furthermore, both group A DC13 parasite lines had higher binding levels to brain endothelial cells (a microvascular niche with limited CD36 expression). This study shows that ICAM-1 is a coreceptor for a subset of EPCR-binding parasites and provides the first evidence of how EPCR and ICAM-1 interact to mediate parasite binding to both resting and TNF-α-activated primary brain and lung endothelial cells. IMPORTANCE Cerebral malaria is a severe neurological complication of P. falciparum infection associated with infected erythrocyte (IE) binding in cerebral vessels. Yet little is known about the mechanisms by which parasites adhere in the brain or other microvascular sites. Here, we studied parasite lines expressing group A DC13-containing PfEMP1 variants, a subset that has previously been shown to have high brain cell- and other endothelial cell-binding activities. We show that DC13-containing PfEMP1 variants have dual EPCR- and ICAM-1-binding activities and that both receptors are involved in parasite adherence to lung and brain endothelial cells. As both EPCR and ICAM-1 are implicated in cerebral malaria, these findings suggest the possibility that parasites with dual binding activities are involved in parasite sequestration to microvascular beds with low CD36 expression, such as the brain, and we urge more research into the multiadhesive properties of PfEMP1 variants.

scholarly journals IL-6 stimulates a concentration-dependent increase in MCP-1 in immortalised human brain endothelial cells

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 270 ◽  
Author(s):  
Jai Min Choi ◽  
Odunayo O. Rotimi ◽  
Simon J. O'Carroll ◽  
Louise F.B. Nicholson
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Systemic Inflammation ◽  
Systemic Circulation ◽  
Dependent Manner ◽  
Brain Endothelial Cells ◽  
Concentration Dependent Manner ◽  
Inflammatory Conditions ◽  
Increased Risk ◽  
The Brain

Systemic inflammation is associated with neurodegeneration, with elevated interleukin-6 (IL-6) in particular being correlated with an increased risk of dementia. The brain endothelial cells of the blood brain barrier (BBB) serve as the interface between the systemic circulation and the brain microenvironment and are therefore likely to be a key player in the development of neuropathology associated with systemic inflammation. Endothelial cells are known to require soluble IL-6 receptor (sIL-6R) in order to respond to IL-6, but studies in rat models have shown that this is not the case for brain endothelial cells and studies conducted in human cells are limited. Here we report for the first time that the human cerebral microvascular cell line, hCMVEC, uses the classical mIL-6R signalling pathway in response to IL-6 in a concentration-dependent manner as measured by the production of monocyte chemotactic protein (MCP-1). This novel finding highlights a unique characteristic of human brain endothelial cells and that further investigation into the phenotype of this cell type is needed to elucidate the mechanisms of BBB pathology in inflammatory conditions.

scholarly journals The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

2020 ◽  
Author(s):  
Josephine Lampe ◽  
Jan Wenzel ◽  
Helge Müller-Fielitz ◽  
Kristin Müller ◽  
Raphael Schuster ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Brain Endothelial Cells ◽  
Brain Pathology ◽  
Interacting Protein ◽  
Small Vessels ◽  
Regulated Cell Death ◽  
Main Protease ◽  
Microvascular Pathology ◽  
The Brain ◽  
Lines Of Evidence

Abstract Several lines of evidence suggest that neurological symptoms in COVID-19 patients are partially due to damage to small vessels. However, the potential mechanisms are unclear. Here, we show that brain endothelial cells express SARS-CoV-2 receptors. The main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of NF-κB signaling. By ablating NEMO, Mpro induces the death of human brain endothelial cells and a microvascular pathology in mice that is similar to what we find in the brain of COVID-19 patients. Importantly, the inhibition of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Our data suggest RIPK as a therapeutic target to treat the neuropathology of COVID-19.

Sign in / Sign up

Export Citation Format

Share Document