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Brain Research Aug 2022The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic... (Review)
Review
The blood-brain barrier (BBB) is a dynamic structure that protects the brain from harmful blood-borne, endogenous and exogenous substances and maintains the homeostatic microenvironment. All constituent cell types play indispensable roles in the BBB's integrity, and other structural BBB components, such as tight junction proteins, adherens junctions, and junctional proteins, can control the barrier permeability. Regarding the need to exchange nutrients and toxic materials, solute carriers, ATP-binding case families, and ion transporter, as well as transcytosis regulate the influx and efflux transport, while the difference in localisation and expression can contribute to functional differences in transport properties. Numerous chemical mediators and other factors such as non-physicochemical factors have been identified to alter BBB permeability by mediating the structural components and barrier function, because of the close relationship with inflammation. In this review, we highlight recently gained mechanistic insights into the maintenance and disruption of the BBB. A better understanding of the factors influencing BBB permeability could contribute to supporting promising potential therapeutic targets for protecting the BBB and the delivery of central nervous system drugs via BBB permeability interventions under pathological conditions.
Topics: Biological Transport; Blood-Brain Barrier; Brain; Humans; Permeability; Tight Junction Proteins; Tight Junctions
PubMed: 35568085
DOI: 10.1016/j.brainres.2022.147937 -
The Journal of Clinical Investigation Nov 2019Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact... (Clinical Trial)
Clinical Trial
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.
Topics: Adherens Junctions; Adult; Aged; Animals; Antigens, CD; Cadherins; Endothelial Cells; Female; Humans; Imatinib Mesylate; Inflammatory Bowel Diseases; Interferon-gamma; Male; Mice; Mice, Knockout; Middle Aged
PubMed: 31566580
DOI: 10.1172/JCI124884 -
Nature Aug 2020The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery. Although the response of epidermal cells to stretching has been...
The ability of the skin to grow in response to stretching has been exploited in reconstructive surgery. Although the response of epidermal cells to stretching has been studied in vitro, it remains unclear how mechanical forces affect their behaviour in vivo. Here we develop a mouse model in which the consequences of stretching on skin epidermis can be studied at single-cell resolution. Using a multidisciplinary approach that combines clonal analysis with quantitative modelling and single-cell RNA sequencing, we show that stretching induces skin expansion by creating a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation. Transcriptional and chromatin profiling identifies how cell states and gene-regulatory networks are modulated by stretching. Using pharmacological inhibitors and mouse mutants, we define the step-by-step mechanisms that control stretch-mediated tissue expansion at single-cell resolution in vivo.
Topics: Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Base Sequence; Cell Cycle Proteins; Cell Differentiation; Cell Self Renewal; Chromatin; Chromatin Assembly and Disassembly; Clone Cells; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Regulatory Networks; Hydrogels; Mechanotransduction, Cellular; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases; Mutation; RNA, Messenger; RNA-Seq; Single-Cell Analysis; Skin; Stem Cells; Trans-Activators; Transcription Factor AP-1; Transcription, Genetic; YAP-Signaling Proteins
PubMed: 32728211
DOI: 10.1038/s41586-020-2555-7 -
Gastroenterology Mar 2021The down-regulated in adenoma (DRA) protein, encoded by SLC26A3, a key intestinal chloride anion exchanger, has recently been identified as a novel susceptibility gene...
BACKGROUND & AIMS
The down-regulated in adenoma (DRA) protein, encoded by SLC26A3, a key intestinal chloride anion exchanger, has recently been identified as a novel susceptibility gene for inflammatory bowel disease (IBD). However, the mechanisms underlying the increased susceptibility to inflammation induced by the loss of DRA remain elusive. Compromised barrier is a key event in IBD pathogenesis. The current studies were undertaken to elucidate the impact of DRA deficiency on epithelial barrier integrity and to define underlying mechanisms.
METHODS
Wild-type and DRA-knockout (KO) mice and crypt-derived colonoids were used as models for intestinal epithelial response. Paracellular permeability was measured by using fluorescein isothiocyanate-dextran flux. Immunoblotting, immunofluorescence, immunohistochemistry, and ribonucleoprotein immunoprecipitation assays were performed. Gut microbiome analysis was conducted to investigate the impact of DRA deficiency on gut microbial communities.
RESULTS
DRA-KO mice exhibited an increased colonic paracellular permeability with significantly decreased levels of tight junction/adherens junction proteins, including ZO-1, occludin, and E-cadherin. A similar expression pattern of occludin and E-cadherin was observed in colonoids derived from DRA-KO mice and short hairpin RNA-mediated DRA knockdown in Caco-2 cells. Microbial analysis showed gut dysbiosis in DRA-KO mice. However, cohousing studies showed that dysbiosis played only a partial role in maintaining tight junction protein expression. Furthermore, our results showed increased binding of RNA-binding protein CUGBP1 with occludin and E-cadherin genes in DRA-KO mouse colon, suggesting that posttranscriptional mechanisms play a key role in gut barrier dysfunction.
CONCLUSIONS
To our knowledge, our studies demonstrate a novel role of DRA in maintaining the intestinal epithelial barrier function and potential implications of its dysregulation in IBD pathogenesis.
Topics: Animals; Antiporters; CELF1 Protein; Caco-2 Cells; Cadherins; Chloride-Bicarbonate Antiporters; Disease Models, Animal; Dysbiosis; Gene Knockdown Techniques; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Male; Mice; Mice, Knockout; Occludin; Permeability; Sulfate Transporters; Tight Junctions
PubMed: 33189700
DOI: 10.1053/j.gastro.2020.11.008 -
Tissue Barriers Jul 2021In some organs, such as the brain, endothelial cells form a robust and highly selective blood-to-tissue barrier. However, in other organs, such as the intestine,... (Review)
Review
In some organs, such as the brain, endothelial cells form a robust and highly selective blood-to-tissue barrier. However, in other organs, such as the intestine, endothelial cells provide less stringent permeability, to allow rapid exchange of solutes and nutrients where needed. To maintain the structural and functional integrity of the highly dynamic blood-brain and gut-vascular barriers, endothelial cells form highly specialized cell-cell junctions, known as adherens junctions and tight junctions. Claudins are a family of four-membrane-spanning proteins at tight junctions and they have both barrier-forming and pore-forming properties. Tissue-specific expression of claudins has been linked to different diseases that are characterized by barrier impairment. In this review, we summarize the more recent progress in the field of the claudins, with particular attention to their expression and function in the blood-brain barrier and the recently described gut-vascular barrier, under physiological and pathological conditions.: 22q11DS 22q11 deletion syndrome; ACKR1 atypical chemokine receptor 1; AD Alzheimer disease; AQP aquaporin; ATP adenosine triphosphate; Aβ amyloid β; BAC bacterial artificial chromosome; BBB blood-brain barrier; C/EBP-α CCAAT/enhancer-binding protein α; cAMP cyclic adenosine monophosphate (or 3',5'-cyclic adenosine monophosphate); CD cluster of differentiation; CNS central nervous system; DSRED discosoma red; EAE experimental autoimmune encephalomyelitis; ECV304 immortalized endothelial cell line established from the vein of an apparently normal human umbilical cord; EGFP enhanced green fluorescent protein; ESAM endothelial cell-selective adhesion molecule; GLUT-1 glucose transporter 1; GVB gut-vascular barrier; H2B histone H2B; HAPP human amyloid precursor protein; HEK human embryonic kidney; JACOP junction-associated coiled coil protein; JAM junctional adhesion molecules; LYVE1 lymphatic vessel endothelial hyaluronan receptor 1; MADCAM1 mucosal vascular addressin cell adhesion molecule 1; MAPK mitogen-activated protein kinase; MCAO middle cerebral artery occlusion; MMP metalloprotease; MS multiple sclerosis; MUPP multi-PDZ domain protein; PATJ PALS-1-associated tight junction protein; PDGFR-α platelet-derived growth factor receptor α polypeptide; PDGFR-β platelet-derived growth factor receptor β polypeptide; RHO rho-associated protein kinase; ROCK rho-associated, coiled-coil-containing protein kinase; RT-qPCR real time quantitative polymerase chain reactions; PDGFR-β soluble platelet-derived growth factor receptor, β polypeptide; T24 human urinary bladder carcinoma cells; TG2576 transgenic mice expressing the human amyloid precursor protein; TNF-α tumor necrosis factor α; WTwild-type; ZO zonula occludens.
Topics: Amyloid beta-Peptides; Animals; Brain; Claudins; Endothelial Cells; Mice; Tight Junctions
PubMed: 34152937
DOI: 10.1080/21688370.2021.1926190 -
Biophysical Reviews Oct 2019Tight junctions (TJ) play a central role in the homeostasis of epithelial and endothelial tissues, by providing a semipermeable barrier to ions and solutes, by... (Review)
Review
Tight junctions (TJ) play a central role in the homeostasis of epithelial and endothelial tissues, by providing a semipermeable barrier to ions and solutes, by contributing to the maintenance of cell polarity, and by functioning as signaling platforms. TJ are associated with the actomyosin and microtubule cytoskeletons, and the crosstalk with the cytoskeleton is fundamental for junction biogenesis and physiology. TJ are spatially and functionally connected to adherens junctions (AJ), which are essential for the maintenance of tissue integrity. Mechano-sensing and mechano-transduction properties of several AJ proteins have been characterized during the last decade. However, little is known about how mechanical forces act on TJ and their proteins, how TJ control the mechanical properties of cells and tissues, and what are the underlying molecular mechanisms. Here I review recent studies that have advanced our understanding of the relationships between mechanical force and TJ biology.
PubMed: 31586306
DOI: 10.1007/s12551-019-00582-7 -
Proceedings of the National Academy of... Jun 2019Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as...
Increased pulmonary microvessel pressure experienced in left heart failure, head trauma, or high altitude can lead to endothelial barrier disruption referred to as capillary "stress failure" that causes leakage of protein-rich plasma and pulmonary edema. However, little is known about vascular endothelial sensing and transduction of mechanical stimuli inducing endothelial barrier disruption. Piezo1, a mechanosensing ion channel expressed in endothelial cells (ECs), is activated by elevated pressure and other mechanical stimuli. Here, we demonstrate the involvement of Piezo1 in sensing increased lung microvessel pressure and mediating endothelial barrier disruption. Studies were made in mice in which Piezo1 was deleted conditionally in ECs ( ), and lung microvessel pressure was increased either by raising left atrial pressure or by aortic constriction. We observed that lung endothelial barrier leakiness and edema induced by raising pulmonary microvessel pressure were abrogated in mice. Piezo1 signaled lung vascular hyperpermeability by promoting the internalization and degradation of the endothelial adherens junction (AJ) protein VE-cadherin. Breakdown of AJs was the result of activation of the calcium-dependent protease calpain and degradation of the AJ proteins VE-cadherin, β-catenin, and p120-catenin. Deletion of Piezo1 in ECs or inhibition of calpain similarly prevented reduction in the AJ proteins. Thus, Piezo1 activation in ECs induced by elevated lung microvessel pressure mediates capillary stress failure and edema formation secondary to calpain-induced disruption of VE-cadherin adhesion. Inhibiting Piezo1 signaling may be a useful strategy to limit lung capillary stress failure injury in response to elevated vascular pressures.
Topics: Adherens Junctions; Animals; Antigens, CD; Arterial Pressure; Blood Pressure; Cadherins; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Female; Gene Knock-In Techniques; Humans; Hydrostatic Pressure; Intercellular Signaling Peptides and Proteins; Ion Channels; Lung; Male; Mechanotransduction, Cellular; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Microvessels; Primary Cell Culture; Pulmonary Edema; Respiratory Insufficiency; Spider Venoms
PubMed: 31186359
DOI: 10.1073/pnas.1902165116 -
International Journal of Molecular... Jan 2020The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective... (Review)
Review
The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads to pathological changes such as tissue inflammation, ion imbalance, and cancer. To better understand the consequences of such malfunctions, the junctional nanoarchitecture is of great importance since it remains so far largely unresolved, mainly because of major difficulties in dynamically imaging these structures at sufficient resolution and with molecular precision. The rapid development of super-resolution imaging techniques ranging from structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single molecule localization microscopy (SMLM) has now enabled molecular imaging of biological specimens from cells to tissues with nanometer resolution. Here we summarize these techniques and their application to the dissection of the nanoscale molecular architecture of TJs and AJs. We propose that super-resolution imaging together with advances in genome engineering and functional analyses approaches will create a leap in our understanding of the composition, assembly, and function of TJs and AJs at the nanoscale and, thereby, enable a mechanistic understanding of their dysfunction in disease.
Topics: Adherens Junctions; Endothelial Cells; Humans; Microscopy, Fluorescence; Single Molecule Imaging; Tight Junctions
PubMed: 31979366
DOI: 10.3390/ijms21030744 -
International Journal of Molecular... Nov 2019Tight junction (TJ) proteins form a continuous intercellular network creating a barrier with selective regulation of water, ion, and solutes across endothelial,... (Review)
Review
Tight junction (TJ) proteins form a continuous intercellular network creating a barrier with selective regulation of water, ion, and solutes across endothelial, epithelial, and glial tissues. TJ proteins include the claudin family that confers barrier properties, members of the MARVEL family that contribute to barrier regulation, and JAM molecules, which regulate junction organization and diapedesis. In addition, the membrane-associated proteins such as MAGUK family members, i.e., zonula occludens, form the scaffold linking the transmembrane proteins to both cell signaling molecules and the cytoskeleton. Most studies of TJ have focused on the contribution to cell-cell adhesion and tissue barrier properties. However, recent studies reveal that, similar to adherens junction proteins, TJ proteins contribute to the control of cell proliferation. In this review, we will summarize and discuss the specific role of TJ proteins in the control of epithelial and endothelial cell proliferation. In some cases, the TJ proteins act as a reservoir of critical cell cycle modulators, by binding and regulating their nuclear access, while in other cases, junctional proteins are located at cellular organelles, regulating transcription and proliferation. Collectively, these studies reveal that TJ proteins contribute to the control of cell proliferation and differentiation required for forming and maintaining a tissue barrier.
Topics: Animals; Cell Differentiation; Cell Proliferation; Humans; Signal Transduction; Tight Junctions; Transcription, Genetic
PubMed: 31783547
DOI: 10.3390/ijms20235972 -
Cells Jun 2020Annexin A2 (AnxA2) is a multifunctional calcium (Ca) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the... (Review)
Review
Annexin A2 (AnxA2) is a multifunctional calcium (Ca) and phospholipid-binding protein that is expressed in a wide spectrum of cells, including those participating in the inflammatory response. In acute inflammation, the interaction of AnxA2 with actin and adherens junction VE-cadherins underlies its role in regulating vascular integrity. In addition, its contribution to endosomal membrane repair impacts several aspects of inflammatory regulation, including lysosome repair, which regulates inflammasome activation, and autophagosome biogenesis, which is essential for macroautophagy. On the other hand, AnxA2 may be co-opted to promote adhesion, entry, and propagation of bacteria or viruses into host cells. In the later stages of acute inflammation, AnxA2 contributes to the initiation of angiogenesis, which promotes tissue repair, but, when dysregulated, may also accompany chronic inflammation. AnxA2 is overexpressed in malignancies, such as breast cancer and glioblastoma, and likely contributes to cancer progression in the context of an inflammatory microenvironment. We conclude that annexin AnxA2 normally fulfills a spectrum of anti-inflammatory functions in the setting of both acute and chronic inflammation but may contribute to disease states in settings of disordered homeostasis.
Topics: Annexin A2; Carrier Proteins; Humans; Inflammation; Neoplasms; Phosphorylation; Tumor Microenvironment
PubMed: 32575495
DOI: 10.3390/cells9061499