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Xuan Cao, Emad Moeendarbary, Philipp Isermann, Patricia M Davidson, Xiao Wang, Michelle B Chen, Anya K Burkart, Jan Lammerding, Roger D Kamm, Vivek B Shenoy
It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alterations that the nucleus encounters can perturb genomic organization that in turn influences cellular behavior. Despite its importance, a biophysical model that connects the experimentally observed nuclear morphological changes to the underlying biophysical factors during transmigration through small constrictions is still lacking...
October 4, 2016: Biophysical Journal
Debashree Goswami, Dietmar Vestweber
The entry of leukocytes into tissues requires well-coordinated interactions between the immune cells and endothelial cells which form the inner lining of blood vessels. The molecular basis for recognition, capture, and adhesion of leukocytes to the endothelial apical surface is well studied. This review will focus on recent advances in our understanding of events following the firm interaction of leukocytes with the inner surface of the blood vessel wall. We will discuss how leukocytes initiate the transmigration (diapedesis) process, trigger the opening of gaps in the endothelial barrier, and eventually move through this boundary...
2016: F1000Research
Viorel Simion, Cristina Ana Constantinescu, Daniela Stan, Mariana Deleanu, Monica Madalina Tucureanu, Elena Butoi, Ileana Manduteanu, Maya Simionescu, Manuela Calin
Inflammation is a common process associated with numerous vascular pathologies. We hypothesized that targeting the inflamed endothelium by coupling a peptide with high affinity for P-selectin to the surface of dexamethasone-loaded lipid nanoemulsions will highly increase their specific binding to activated endothelial cells (EC) and reduce the cell activation. We developed and characterized dexamethasone-loaded lipid nanoemulsions directed towards P-selectin (PLN-Dex) and monitored their anti-inflammatory effects in vitro using cultured EC (EA...
2016: Mediators of Inflammation
Angela R M Kurz, Monika Pruenster, Ina Rohwedder, Mahalakshmi Ramadass, Kerstin Schäfer, Ute Harrison, Gabriel Gouveia, Claudia Nussbaum, Roland Immler, Johannes R Wiessner, Andreas Margraf, Dae-Sik Lim, Barbara Walzog, Steffen Dietzel, Markus Moser, Christoph Klein, Dietmar Vestweber, Rainer Haas, Sergio D Catz, Markus Sperandio
Neutrophils need to penetrate the perivascular basement membrane for successful extravasation into inflamed tissue, but this process is incompletely understood. Recent findings have associated mammalian sterile 20-like kinase 1 (MST1) loss of function with a human primary immunodeficiency disorder, suggesting that MST1 may be involved in immune cell migration. Here, we have shown that MST1 is a critical regulator of neutrophil extravasation during inflammation. Mst1-deficient (Mst1-/-) neutrophils were unable to migrate into inflamed murine cremaster muscle venules, instead persisting between the endothelium and the basement membrane...
October 4, 2016: Journal of Clinical Investigation
Isao Matsuo, Ryuji Hiramatsu
In most mammals, embryonic development and growth proceed in the maternal uterus. Mouse late blastocyst embryos implant on the uterine epithelium around embryonic day (E)4.5, and immediately afterward the whole embryo's shape is dynamically changed from a bowl-like shape to an elongated egg-cylinder until E5.5. Concurrently, mouse anterior-posterior (A-P) axis polarization occurs by the emergence of distal visceral endoderm (DVE) cells at the cellular and molecular levels as the proximal-distal (P-D) axis. The embryonic growth and axis polarization are considered to be controlled primarily by multiple growth factors' signaling...
September 30, 2016: Mechanisms of Development
Martina Di Modica, Viola Regondi, Marco Sandri, Marilena V Iorio, Adriana Zanetti, Elda Tagliabue, Patrizia Casalini, Tiziana Triulzi
Exosomes-secreted microRNAs play an important role in metastatic spread. During this process breast cancer cells acquire the ability to transmigrate through blood vessels by inducing changes in the endothelial barrier. We focused on miR-939 that is predicted to target VE-cadherin, a component of adherens junction involved in vessel permeability. By in silico analysis miR-939 was found highly expressed in the basal-like tumor subtypes and in our cohort of 63 triple-negative breast cancers (TNBCs) its expression significantly interacted with lymph node status in predicting disease-free survival probability...
September 28, 2016: Cancer Letters
Jiannan Chen, Xiangjian Zhang, Cong Zhang, Wenhui Wang, Rong Chen, Honglei Jiao, Linlin Li, Lan Zhang, Lili Cui
Inflammation after stroke consists of activation of microglia/astrocytes in situ and infiltration of blood-borne leukocytes, resulting in brain damage and neurological deficits. Mounting data demonstrated that most natural components from medicinal plants had anti-inflammatory effects after ischemic stroke through inhibiting activation of resident microglia/astrocytes within ischemic area. However, it is speculated that this classical activity cannot account for the anti-inflammatory function of these natural components in the cerebral parenchyma, where they are detected at very low concentrations due to their poor membrane permeability and slight leakage of BBB...
2016: Mediators of Inflammation
Jochen A S Lamote, Sarah Glorieux, Hans J Nauwynck, Herman W Favoreel
: Passage of the basement membrane (BM), which forms a barrier between epithelium and underlying lamina propria, represents an important step in the early pathogenesis of different alphaherpesviruses. Rho-GTPase signaling plays an important role in transmigration of cells across the BM during physiological and pathological processes. We reported earlier that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) interferes with Rho GTPase signaling and causes a reorganisation of the host cell cytoskeleton which, as a consequence, enhances viral cell-to-cell spread in epithelial cell cultures...
September 28, 2016: Journal of Virology
Chi Huu Nguyen, Stefan Brenner, Nicole Huttary, Atanas Georgiev Atanasov, Verena Maria Dirsch, Waranya Chatuphonprasert, Sivio Holzner, Serena Stadler, Juliane Riha, Sigurd Krieger, Rainer de Martin, Zsuzsanna Bago-Horvath, Georg Krupitza, Walter Jäger
A causal link between overexpression of aryl hydrocarbon receptor (AHR) and its target cytochrome P450 1A1 (CYP1A1) and metastatic outgrowth of various cancer entities has been established. Nevertheless, the mechanism how AHR/CYP1A1 support metastasis formation is still little understood. In vitro we discovered a potential mechanism facilitating tumour dissemination based on the production of 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). Utilising a three-dimensional lymph endothelial cell (LEC) monolayer & MDA-MB231 breast cancer cell spheroid co-culture model in combination with knock-down approach allowed elucidation of the molecular/biochemical basis of AHR/CYP1A1-induced tumour breaching through the LEC barrier...
September 27, 2016: Human Molecular Genetics
Luisa Klotz, Ivan Kuzmanov, Stephanie Hucke, Catharina C Gross, Vilmos Posevitz, Angela Dreykluft, Andreas Schulte-Mecklenbeck, Claudia Janoschka, Maren Lindner, Martin Herold, Nicholas Schwab, Isis Ludwig-Portugall, Christian Kurts, Sven G Meuth, Tanja Kuhlmann, Heinz Wiendl
Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the blood-brain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice)...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Silvio Holzner, Daniel Senfter, Serena Stadler, Anna Staribacher, Chi Huu Nguyen, Anna Gaggl, Silvana Geleff, Nicole Huttary, Sigurd Krieger, Walter Jäger, Helmut Dolznig, Robert M Mader, Georg Krupitza
Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three‑dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)‑barrier breaching to study mechanisms of intra‑/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5‑fluorouracil (5‑FU)‑resistant CRC CCL227 cells...
September 20, 2016: Oncology Reports
Grazia Maugeri, Agata Grazia D'Amico, Salvatore Saccone, Concetta Federico, Sebastiano Cavallaro, Velia D'Agata
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) exert a protective role against retinal injuries, including diabetic macular edema (DME). The macular damage is induced by hyperglycemia, which damages vessels supplying blood to the retina and induces hypoxia. The microenvironmental changes stimulate the expression of hypoxia-inducible factors (HIFs), which promote the choroidal endothelial cell transmigration across the retinal pigmented epithelium (RPE) into neurosensory retina, where they proliferate into new vessels under stimulation of the vascular endothelial growth factor (VEGF)...
September 23, 2016: Journal of Cellular Physiology
Julie Y Zhou, Taylor P Szasz, Phillip J Stewart-Hutchinson, Janardan Sivapalan, Elizabeth M Todd, Lauren E Deady, John A Cooper, Michael D Onken, S Celeste Morley
Elucidating the molecular regulation of macrophage migration is essential for understanding the pathophysiology of multiple human diseases, including host responses to infection and autoimmune disorders. Macrophage migration is supported by dynamic rearrangements of the actin cytoskeleton, with formation of actin-based structures such as podosomes and lamellipodia. Here we provide novel insights into the function of the actin-bundling protein l-plastin (LPL) in primary macrophages. We found that podosome stability is disrupted in primary resident peritoneal macrophages from LPL(-/-) mice...
October 2016: Molecular Immunology
Haibo Wang, Xiaokun Han, Colin A Bretz, Silke Becker, Deeksha Gambhir, George W Smith, R Jude Samulski, Erika S Wittchen, Lawrence A Quilliam, Magdalena Chrzanowska-Wodnicka, M Elizabeth Hartnett
To test the hypothesis that increased Rap1a activity specifically in retinal pigment epithelial cells resists choroidal neovascularization (CNV), self-complementary adeno-associated virus 2 (scAAV2) with RPE65-promoter-driven GFP vectors were generated and introduced subretinally into Rap1b-deficient mice. Six-week-old mice that received subretinal control (scAAV2-Con) or constitutively active Rap1a (scAAV2-CARap1a) showed strong GFP at the 5 × 10(8) viral particle/µl dose 5 weeks later without altering retinal morphology or function...
2016: Molecular Therapy. Methods & Clinical Development
Lionel Guillou, Avin Babataheri, Michael Saitakis, Armelle Bohineust, Stéphanie Dogniaux, Claire Hivroz, Abdul I Barakat, Julien Husson
T lymphocytes in the human body routinely undergo large deformations, both passively when going through narrow capillaries and actively when transmigrating across endothelial cells or squeezing through tissue. We investigate physical factors that enable and limit such deformations and explore how passive and active deformations may differ. Employing micropipette aspiration to mimic squeezing through narrow capillaries, we find that T lymphocytes maintain a constant volume while increasing their apparent membrane surface area upon aspiration...
September 7, 2016: Molecular Biology of the Cell
Mahdi Ahmadi, Reza Rahbarghazi, Sina Soltani, Mohammad Reza Aslani, Rana Keyhanmanesh
Our aim in selecting an appropriate cell fraction and conditioned media (CM) was to achieve the suitable candidate for ameliorating long-term chronic asthmatic changes of respiratory tract. Thirty-six rats were classified into healthy and sensitized groups, which were further divided into three subgroups; rats received systemically 50 μl volume of PBS, CM, or 2 × 10(6) rat bone marrow-derived mesenchymal stem cells (rBMMSCs). Tracheal responsiveness (TR), immunologic responses, and recruitment of rBMMSCs into the lungs were evaluated...
September 2, 2016: Inflammation
Sergiy Yakovlev, Alexey M Belkin, Ling Chen, Chunzhang Cao, Li Zhang, Dudley K Strickland, Leonid Medved
Our previous studies revealed that the interaction of fibrin with the very low density lipoprotein receptor (VLDLR) promotes transendothelial migration of leukocytes and thereby inflammation, and localised the fibrin-binding site to CR-domains 2-4 of this receptor. In the present study, we tested interaction of three anti-VLDLR monoclonal antibodies, mAb 1H10, 1H5, and 5F3, with recombinant fragments of VLDLR containing various combinations of its CR-domains and found that the epitopes for mAb 1H10 and mAb 1H5 overlap with the fibrin-binding site of VLDLR...
September 1, 2016: Thrombosis and Haemostasis
Kristina J H Kleinwort, Barbara Amann, Stefanie M Hauck, Regina Feederle, Walter Sekundo, Cornelia A Deeg
PURPOSE: Recently, formation of tertiary lymphoid structures was demonstrated and further characterized in the R161H mouse model of spontaneous autoimmune uveitis. In the horse model of spontaneous recurrent uveitis, intraocular lymphoid follicle formation is highly characteristic, and found in all stages and scores of disease, but in depth analyses of immunologic features of these structures are lacking to date. METHODS: Paraffin-embedded eye sections of cases with equine spontaneous recurrent uveitis (ERU) were characterized with immunohistochemistry to gain insight into the distribution, localization, and signaling of immune cells in intraocular tertiary lymphoid tissues...
August 1, 2016: Investigative Ophthalmology & Visual Science
Roland Csépányi-Kömi, Éva Wisniewski, Balázs Bartos, Petra Lévai, Tamás Németh, Bernadett Balázs, Angela R M Kurz, Susanne Bierschenk, Markus Sperandio, Erzsébet Ligeti
ARHGAP25 is a Rac-specific GTPase-activating protein that is expressed primarily in hematopoietic cells. The involvement of ARHGAP25 in regulating the recruitment of leukocytes to inflammatory sites was investigated in genetically modified mice. Using intravital microscopy, we show that Arhgap25 deficiency affects all steps of leukocyte recruitment with a predominant enhancement of transendothelial migration of neutrophilic granulocytes. Increased transmigration of Arhgap25-deficient leukocytes is demonstrated in inflamed cremaster muscle venules, in a peritonitis model, and in an in vitro chemotaxis assay...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ji-Young Choi, Sangmee Ahn Jo
Intercellular adhesion molecule1 (ICAM1) is involved in adhesion and transmigration of leukocytes across endothelium, promoting brain inflammation and leading to brain diseases. Here, we studied the mechanism that regulates ICAM expression in response to proinflammatory cytokine tumor necrosis factor alpha (TNF-α). ICAM1 mRNA and protein levels in human brain microvascular endothelial cells dramatically increased after TNF-α treatment. TNF-α also upregulated histone demethylases KDM1B and KDM7A responsible for demethylation of H3K9me2, a well-known repression marker...
September 23, 2016: Biochemical and Biophysical Research Communications
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