Investigation of Evolutionary History and Origin of the Tre1 Family Suggests a Role in Regulating Hemocytes Cells Infiltration of the Blood–Brain Barrier

Understanding the evolutionary relationship between immune cells and the blood–brain barrier (BBB) is important to devise therapeutic strategies. In vertebrates, immune cells follow either a paracellular or a transcellular pathway to infiltrate the BBB. In Drosophila, glial cells form the BBB that regulates the access of hemocytes to the brain. However, it is still not known which diapedesis route hemocytes cells follow. In vertebrates, paracellular migration is dependent on PECAM1, while transcellular migration is dependent on the expression of CAV1. Interestingly Drosophila genome lacks both genes. Tre1 family (Tre1, moody, and Dmel_CG4313) play a diverse role in regulating transepithelial migration in Drosophila. However, its evolutionary history and origin are not yet known. We performed phylogenetic analysis, together with HH search, positive selection, and ancestral reconstruction to investigate the Tre1 family. We found that Tre1 exists in Mollusca, Arthropoda, Ambulacraria, and Scalidophora. moody is shown to be a more ancient protein and it has existed since Cnidaria emergence and has a homolog (e.g., GPCR84) in mammals. The third family member (Dmel_CG4313) seems to only exist in insects. The origin of the family seems to be related to the rhodopsin-like family and in particular family α. We found that opsin is the nearest receptor to have a common ancestor with the Tre1 family that has diverged in sponges. We investigated the positive selection of the Tre1 family using PAML. Tre1 seems to have evolved under negative selection, whereas moody has evolved during positive selection. The sites that we found under positive selection are likely to play a role in the speciation of function in the case of moody. We have identified an SH3 motif, in Tre1 and, moody and Dmel_CG4313. SH3 is known to play a fundamental role in regulating actin movement in a Rho-dependent manner in PECAM1. Our results suggest that the Tre1 family could be playing an important role in paracellular diapedesis in Drosophila.

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Evolutionary history and origin of Tre1 superfamily shed light on its role in regulating blood brain barrier

10.1101/2021.04.29.441935 ◽

2021 ◽

Author(s):

Norwin Kubick ◽

Pavel Klimovich ◽

Irmina Bieńkowska ◽

Mariusz Sacharczuk ◽

Michel-Edwar Mickael

Keyword(s):

Positive Selection ◽

Immune Cells ◽

Evolutionary History ◽

Evolutionary Relationship ◽

Drosophila Genome ◽

Dependent Manner ◽

Ancestral Reconstruction ◽

Critical Function ◽

Blood Brain ◽

Drosophila Brain

Understanding how the evolutionary relationship between immune cells and the blood-brain is important to devise therapeutic strategies that can regulate their critical function. In vertebrates, immune cells follow either a paracellular or transcellular pathway to infiltrate the BBB. In drosophila glial cells form the BBB that regulates the access of immune-like cells to the drosophila brain. However, it is still not known which route immune-like cells follow to infiltrate the drosophila brain. In vertebrates, paracellular migration is dependent on PECAM1, while transcellular migration is dependent on the expression of CAV1. Interestingly drosophila genome lacks both genes. Tre1 superfamily (Tre1, Moody, and Dmel_CG4313) play a diverse role in regulating transepithelial migration in drosophila. However, its evolutionary history and origin are not yet known. We performed phylogenetic analysis, together with HH search, positive selection, and ancestral reconstruction to investigate the Tre1 family Interestingly we found that Tre1 exists in mollusks, insects, ambulacria, and sclaidphora. Moody is shown to be a more ancient protein and it existed since cnidaria emergence and has a homolog (GPCR84) in mammals. The third family member (Dmel_CG4313) only exists in insects. The origin of the family seems to be related to the rhodopsin-like family and in particular family α. We found that opsin is the nearest receptor to have a common ancestor with the Tre1 superfamily that seems to have diverged in sponges. We investigated the positive selection of the Tre1 family using PAML. Tre1 seems to have evolved under negative selection, whereas Moody has evolved during positive selection. The sites that we found under positive selection are Likely to play a role in the speciation of function in the case of Moody. We have identified an SH3, in Tre1 and, moody and Dmel_CG4313. Sh3 is known to play a fundamental role in regulating actin movement in a Rho-dependent manner. We suggest that Tre1 could be playing an important role in paracellular diapedesis in drosophila.

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BACTERIOPHAGAL INFECTION OF RAT INTESTINAL MICROBIOTA INCREASES THE PERMEABILITY OF THE BLOOD-BRAIN BARRIER AND MIGRATION OF IMMUNE CELLS INTO THE BRAIN PARENCHYMA

Neuroscience for Medicine and Psychology ◽

10.29003/m548.sudak.ns2019-15/368-369 ◽

2019 ◽

Author(s):

Tatyana Sergeyeva ◽

Valeriy Sergeyev ◽

Julia Kyznecova

Keyword(s):

Blood Brain Barrier ◽

Intestinal Microbiota ◽

Immune Cells ◽

Brain Parenchyma ◽

Brain Barrier ◽

Blood Brain ◽

And Migration ◽

The Brain

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Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

10.1101/2020.10.08.332007 ◽

2020 ◽

Author(s):

Alejandra Palomino-Antolin ◽

Paloma Narros-Fernández ◽

Víctor Farré-Alins ◽

Javier Sevilla-Montero ◽

Celine Decouty-Pérez ◽

...

Keyword(s):

Brain Injury ◽

Blood Brain Barrier ◽

Inflammatory Cytokines ◽

Nlrp3 Inflammasome ◽

Neurovascular Unit ◽

Time Dependent ◽

Brain Barrier ◽

Dependent Manner ◽

Dual Effect ◽

Blood Brain

AbstractBackground and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

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Rufinamide (RUF) suppresses inflammation and maintains the integrity of the blood–brain barrier during kainic acid-induced brain damage

Open Life Sciences ◽

10.1515/biol-2021-0090 ◽

2021 ◽

Vol 16 (1) ◽

pp. 845-855

Author(s):

Huaxu Yu ◽

Bin He ◽

Xu Han ◽

Ting Yan

Keyword(s):

Kainic Acid ◽

Blood Brain Barrier ◽

Neuronal Damage ◽

Brain Barrier ◽

Protective Mechanism ◽

Dependent Manner ◽

Nissl Staining ◽

Microglia Cell ◽

Protein Levels ◽

Blood Brain

Abstract Rufinamide (RUF) is a structurally unique anti-epileptic drug, but its protective mechanism against brain injury remains unclear. In the present study, we validated how the RUF protected mice with kainic acid (KA)-induced neuronal damage. To achieve that, a mouse epilepsy model was established by KA intraperitoneal injection. After Nissl staining, although there was a significant reduction in Nissl bodies in mice treated with KA, 40, 80, and 120 mg/kg, RUF significantly reduced KA-induced neuronal damage, in a dose-dependent manner. Among them, 120 mg/kg RUF was most pronounced. Immunohistochemistry (IHC) and western blot analysis showed that RUF inhibited the IBA-1 overexpression caused by KA to block microglia cell overactivation. Further, RUF treatment partially reversed neuroinflammatory cytokine (IL-1β, TNFα, HMGB1, and NLRP3) overexpression in mRNA and protein levels in KA mice. Moreover, although KA stimulation inhibited the expression of tight junctions, RUF treatment significantly upregulated expression of tight junction proteins (occludin and claudin 5) in both mRNA and protein levels in the brain tissues of KA mice. RUF inhibited the overactivation of microglia, suppressed the neuroinflammatory response, and reduced the destruction of blood–brain barrier, thereby alleviating the excitatory nerve damage of the KA-mice.

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Flavonoid transport across RBE4 cells: A blood-brain barrier model

Cellular & Molecular Biology Letters ◽

10.2478/s11658-010-0006-4 ◽

2010 ◽

Vol 15 (2) ◽

Cited By ~ 61

Author(s):

Ana Faria ◽

Diogo Pestana ◽

Diana Teixeira ◽

Joana Azevedo ◽

Victor Freitas ◽

...

Keyword(s):

Blood Brain Barrier ◽

Cerebrovascular Diseases ◽

Brain Barrier ◽

Array Detector ◽

Dependent Manner ◽

Blood Brain ◽

Parkinson’S Diseases ◽

Blood Brain Barrier Model ◽

Immortalized Cell ◽

Barrier Model

AbstractThere is a growing interest in dietary therapeutic strategies to combat oxidative stress-induced damage to the Central Nervous System (CNS), which is associated with a number of pathophysiological processes, including Alzheimer’s and Parkinson’s diseases and cerebrovascular diseases. Identifying the mechanisms associated with phenolic neuroprotection has been delayed by the lack of information concerning the ability of these compounds to enter the CNS. The aim of this study was to evaluate the transmembrane transport of flavonoids across RBE-4 cells (an immortalized cell line of rat cerebral capillary endothelial cells) and the effect of ethanol on this transport. The detection and quantification of all of the phenolic compounds in the studied samples (basolateral media) was performed using a HPLC-DAD (Diode Array Detector). All of the tested flavonoids (catechin, quercetin and cyanidin-3-glucoside) passed across the RBE-4 cells in a time-dependent manner. This transport was not influenced by the presence of 0.1% ethanol. In conclusion, the tested flavonoids were capable of crossing this blood-brain barrier model.

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Penetration of the blood-brain barrier: enhancement of drug delivery and imaging by bacterial glycopeptides.

Journal of Experimental Medicine ◽

10.1084/jem.182.4.1037 ◽

1995 ◽

Vol 182 (4) ◽

pp. 1037-1043 ◽

Cited By ~ 28

Author(s):

B Spellerberg ◽

S Prasad ◽

C Cabellos ◽

M Burroughs ◽

P Cahill ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Parenchyma ◽

Brain Barrier ◽

Dependent Manner ◽

Pharmacological Agents ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Blood Brain ◽

Brain Barrier Permeability ◽

The Brain

The blood-brain barrier restricts the passage of many pharmacological agents into the brain parenchyma. Bacterial glycopeptides induce enhanced blood-brain barrier permeability when they are present in the subarachnoid space during meningitis. By presenting such glycopeptides intravenously, blood-brain barrier permeability in rabbits was enhanced in a reversible time- and dose-dependent manner to agents < or = 20 kD in size. Therapeutic application of this bioactivity was evident as enhanced penetration of the antibiotic penicillin and the magnetic resonance imaging contrast agent gadolinium-diethylene-triamine-pentaacetic acid into the brain parenchyma.

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Abstract 218: Pericytic Laminin Regulates Blood-Brain Barrier Integrity in an Age-Dependent Manner

Stroke ◽

10.1161/str.48.suppl_1.218 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Yao Yao ◽

Jyoti Gautam ◽

Xuanming Zhang

Keyword(s):

Endothelial Cells ◽

Basement Membrane ◽

Blood Brain Barrier ◽

Vessel Density ◽

Brain Barrier ◽

Dependent Manner ◽

Vascular Integrity ◽

Blood Brain ◽

Age Dependent

Introduction: Laminin, a major component of the basement membrane, plays an important role in blood brain barrier (BBB) regulation. At the neurovascular unit, astrocytes, brain endothelial cells, and pericytes synthesize and deposit different laminin isoforms into the basement membrane. Previous studies from our laboratory showed that loss of astrocytic laminin induces age-dependent and region-specific BBB breakdown and intracerebral hemorrhage, suggesting a critical role of astrocytic laminin in vascular integrity maintenance. Laminin α4 (predominantly generated by endothelial cells) has been shown to regulate vascular integrity at embryonic/neonatal stage. The role of pericytic laminin in vascular integrity, however, remains elusive. Methods: We investigated the function of pericyte-derived laminin in vascular integrity using laminin conditional knockout mice. Specifically, laminin floxed mice were crossed with PDGFRβ-Cre line to generate mutants (PKO) with laminin deficiency in PDGFRβ + cells, which include both pericytes and vascular smooth muscle cells (vSMCs). To distinguish the contribution of pericyte- and vSMC-derived laminin, we also generated a vSMC-specific condition knockout line (TKO) by crossing the laminin floxed mice with Transgelin-Cre mice. In this study, mice of both genders on a C57Bl6 background were used. At least 5-6 animals were used in biochemical and histological analyses in this study. Results: Pericyte-derived laminin was abrogated in all PKO mice. However, only old but not young PKO mice showed signs of BBB breakdown and reduced vessel density, suggesting age-dependent changes. Consistent with these data, further mechanistic studies revealed reduced tight junction proteins, diminished AQP4 expression, and deceased pericyte coverage in old but not young PKO mice. In addition, neither BBB disruption nor decreased vessel density was observed in TKO mice, suggesting that these vascular defects are due to loss of pericyte- rather than vSMC-derived laminin. Conclusions: These results strongly suggest that pericyte-derived laminin active regulates BBB integrity and vessel density in an age-dependent manner. I would like this abstract to be considered for the Stroke Basic Science Award.

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