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E J Meester, B J Krenning, R H de Blois, J P Norenberg, M de Jong, M R Bernsen, K Van der Heiden
BACKGROUND: 111 In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated111 In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: ApoE-/- mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of111 In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of111 In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1...
March 13, 2018: Journal of Nuclear Cardiology: Official Publication of the American Society of Nuclear Cardiology
Mehmet Sen, Adem C Koksal, Koichi Yuki, Jianchuan Wang, Timothy A Springer
In αI integrins including leukocyte function-associated antigen-1 (LFA-1), ligand-binding function is delegated to the αI domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the αI domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the αI domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM-1) to the αI domain is linked to headpiece opening and engenders a preferred αI domain orientation...
March 5, 2018: Journal of Biological Chemistry
Dehua Liu, Ben Chung-Lap Chan, Ling Cheng, Miranda Sin-Man Tsang, Jing Zhu, Chun-Wai Wong, Delong Jiao, Helen Yau-Tsz Chan, Ping Chung Leung, Christopher Wai-Kei Lam, Chun Kwok Wong
The immune system responds to Mycobacterium tuberculosis (MTB) infection by forming granulomas to quarantine the bacteria from spreading. Granuloma-mediated inflammation is a cause of lung destruction and disease transmission. Sophora flavescens (SF) has been demonstrated to exhibit bactericidal activities against MTB. However, its immune modulatory activities on MTB-mediated granulomatous inflammation have not been reported. In the present study, we found that flavonoids from Sophora flavescens (FSF) significantly suppressed the pro-inflammatory mediators released from mouse lung alveolar macrophages (MH-S) upon stimulation by trehalose dimycolate (TDM), the most abundant lipoglycan on MTB surface...
March 2, 2018: Scientific Reports
Jonathan O Martinez, Roberto Molinaro, Kelly A Hartman, Christian Boada, Roman Sukhovershin, Enrica De Rosa, Dickson Kirui, Shanrong Zhang, Michael Evangelopoulos, Angela M Carter, James A Bibb, John P Cooke, Ennio Tasciotti
Activation of the vascular endothelium is characterized by increased expression of vascular adhesion molecules and chemokines. This activation occurs early in the progression of several diseases and triggers the recruitment of leukocytes. Inspired by the tropism of leukocytes, we investigated leukocyte-based biomimetic nanoparticles (i.e., leukosomes) as a novel theranostic platform for inflammatory diseases. Methods : Leukosomes were assembled by combining phospholipids and membrane proteins from leukocytes...
2018: Theranostics
Anika Hain, Melanie Krämer, René M Linka, Saeideh Nakhaei-Rad, Mohammad Reza Ahmadian, Dieter Häussinger, Arndt Borkhardt, Carsten Münk
Successful replication of Human immunodeficiency virus (HIV)-1 depends on the expression of various cellular host factors, such as the interleukin-2 inducible T-cell kinase (ITK), a member of the protein family of TEC-tyrosine kinases. ITK is selectively expressed in T-cells and coordinates signaling pathways downstream of the T-cell receptor and chemokine receptors, including PLC-1 activation, Ca 2+ -release, transcription factor mobilization, and actin rearrangements. The exact role of ITK during HIV-1 infection is still unknown...
February 16, 2018: Scientific Reports
Travis I Moore, Jesse Aaron, Teng-Leong Chew, Timothy A Springer
We use super-resolution interferometric photoactivation and localization microscopy (iPALM) and a constrained photoactivatable fluorescent protein integrin fusion to measure the displacement of the head of integrin lymphocyte function-associated 1 (LFA-1) resulting from integrin conformational change on the cell surface. We demonstrate that the distance of the LFA-1 head increases substantially between basal and ligand-engaged conformations, which can only be explained at the molecular level by integrin extension...
February 13, 2018: Cell Reports
A J Davenport, R S Cross, K A Watson, Y Liao, W Shi, H M Prince, P A Beavis, J A Trapani, M H Kershaw, D S Ritchie, P K Darcy, P J Neeson, M R Jenkins
Chimeric antigen receptor T (CAR-T) cells are effective serial killers with a faster off-rate from dying tumor cells than CAR-T cells binding target cells through their T cell receptor (TCR). Here we explored the functional consequences of CAR-mediated signaling using a dual-specific CAR-T cell, where the same cell was triggered via TCR (tcrCTL) or CAR (carCTL). The carCTL immune synapse lacked distinct LFA-1 adhesion rings and was less reliant on LFA to form stable conjugates with target cells. carCTL receptors associated with the synapse were found to be disrupted and formed a convoluted multifocal pattern of Lck microclusters...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Maryam Abdullahi, Fisayo A Olotu, Mahmoud E Soliman
Lymphocyte Function Associated antigen-1(LFA-1) has been implicated severely in the pathophysiology of inflammatory and autoimmune diseases. Its active and inactive conformations correlate with its diseased and non-diseased state respectively. This is determined by its degree of affinity for its intrinsic ligand (ICAM) at the active site and accompanying synergistic coordination at the α7 helix. This potentiates the role of inhibitors in disrupting this interaction allosterically. Herein, we present a first account of the structural dynamics which characterizes the inhibitory effect of a novel LFA-1 antagonist, Lifitegrast (SAR1118), upon binding to the I-domain allosteric site (IDAS) using molecular dynamics simulation...
February 5, 2018: Computational Biology and Chemistry
Sara W Feigelson, Adam Solomon, Adi Biram, Miki Hatzav, Moria Lichtenstein, Ofer Regev, Stav Kozlovski, Diana Varol, Caterina Curato, Dena Leshkowitz, Steffen Jung, Ziv Shulman, Ronen Alon
Protective immune responses depend on the formation of immune synapses between T cells and antigen-presenting cells (APCs). The two main LFA-1 ligands, ICAM-1 and ICAM-2, are co-expressed on many cell types, including APCs and blood vessels. Although these molecules were suggested to be key players in immune synapses studied in vitro, their contribution to helper T cell priming in vivo is unclear. Here, we used transgenic mice and intravital imaging to examine the role of dendritic cell (DC) ICAM-1 and ICAM-2 in naive CD4 T cell priming and differentiation in skin-draining lymph nodes...
January 23, 2018: Cell Reports
Alessandra Bertoni, Oscar Alabiso, Alessandra Silvia Galetto, Gianluca Baldanzi
From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLβ2 integrin) and VLA-4 (α4β1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor...
February 6, 2018: International Journal of Molecular Sciences
Katarzyna I Jankowska, Edward K Williamson, Nathan H Roy, Daniel Blumenthal, Vidhi Chandra, Tobias Baumgart, Janis K Burkhardt
Full T cell activation requires coordination of signals from multiple receptor-ligand pairs that interact in parallel at a specialized cell-cell contact site termed the immunological synapse (IS). Signaling at the IS is intimately associated with actin dynamics; T cell receptor (TCR) engagement induces centripetal flow of the T cell actin network, which in turn enhances the function of ligand-bound integrins by promoting conformational change. Here, we have investigated the effects of integrin engagement on actin flow, and on associated signaling events downstream of the TCR...
2018: Frontiers in Immunology
Raïssa Houmadi, Delphine Guipouy, Javier Rey-Barroso, Zilton Vasconcelos, Julie Cornet, Manoel Manghi, Nicolas Destainville, Salvatore Valitutti, Sophie Allart, Loïc Dupré
T lymphocyte cytotoxicity relies on a synaptic ring of lymphocyte function-associated antigen 1 (LFA-1), which permits polarized delivery of lytic granules. How LFA-1 organization is controlled by underlying actin cytoskeleton dynamics is poorly understood. Here, we explored the contribution of the actin cytoskeleton regulator WASP to the topography of LFA-1 using a combination of microscopy modalities. We uncover that the reduced cytotoxicity of Wiskott-Aldrich syndrome patient-derived CD8+ T lymphocytes lacking WASP is associated with reduced LFA-1 activation, unstable synapse, and delayed lethal hit...
January 23, 2018: Cell Reports
Ning Li, Hao Yang, Manliu Wang, Shouqin Lü, Yan Zhang, Mian Long
Lymphocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1), and their counter-receptors such as intercellular cell adhesion molecule (ICAM)-1 and ICAM-2, junctional adhesion molecule (JAM)-A, JAM-C and receptor for advanced glycation end products (RAGE) are crucial to promote polymorphonuclear leukocyte (neutrophil, PMN) recruitment. The underlying mechanisms of ligand-specific bindings in this cascade remain incompletely known. We compared the dynamic force spectrum for various LFA-1/Mac-1-ligand bonds using single molecule atomic force microscopy (AFM) and tested their functions to mediate PMN recruitment under in vitro shear flow...
December 27, 2017: Molecular Biology of the Cell
Kerry Tedford, Michael Steiner, Stanislav Koshutin, Karin Richter, Laura Tech, Yannik Eggers, Inga Jansing, Kerstin Schilling, Anja Erika Hauser, Mark Korthals, Klaus-Dieter Fischer
Splenic marginal zone B cells (MZB) shuttle between the blood-filled marginal zone for antigen collection and the follicle for antigen delivery. However, it is unclear how MZBs migrate directionally from the marginal zone to the follicle. Here, we show that murine MZBs migrate up shear flow via the LFA-1 (αLβ2) integrin ligand ICAM-1, but adhere or migrate down the flow via the VLA-4 integrin (α4β1) ligand VCAM-1. MZBs lacking Arhgef6 (Pak-interacting exchange factor (αPIX)) or functional LFA-1 are impaired in shuttling due to mislocalization toward the VCAM-1-rich red pulp...
December 22, 2017: Nature Communications
Justyna M Meissner, Aleksander F Sikorski, Tomasz Nawara, Jakub Grzesiak, Krzysztof Marycz, Dżamila M Bogusławska, Izabela Michalczyk, Marie-Christine Lecomte, Beata Machnicka
T-lymphocyte activation after antigen presentation to the T-Cell Receptor (TCR) is a critical step in the development of proper immune responses to infection and inflammation. This dynamic process involves reorganization of the actin cytoskeleton and signaling molecules at the cell membrane, leading to the formation of the Immunological Synapse (IS). The mechanisms regulating the formation of the IS are not completely understood. Nonerythroid spectrin is a membrane skeletal protein involved in the regulation of many cellular processes, including cell adhesion, signaling and actin cytoskeleton remodeling...
2017: PloS One
Wei Gao, Qiu-Ming Meng, Xiao-Guang Cui
PURPOSE: Lung ischemia-reperfusion injury (LIRI) after lung transplantation can lead to primary graft dysfunction. Budesonide can improve endothelial function to reduce lung injury. This study was aimed to examine the effects of budesonide on LIRI and potential mechanisms. METHODS: Wistar rats were randomized and transplanted with syngeneic left lung or received the sham surgery. The recipients were instilled with saline or budesonide immediately after reperfusion...
December 13, 2017: Experimental Lung Research
Malin Samuelsson, Katarzyna Potrzebowska, Janne Lehtonen, Jason P Beech, Ekatarina Skorova, Heli Uronen-Hansson, Lena Svensson
The regulation of cell adhesion and motility is complex and requires the intracellular trafficking of integrins to and from sites of cell adhesion, especially in fast-moving cells such as leukocytes. The Rab family of guanosine triphosphatases (GTPases) is essential for vesicle transport, and vesicles mediate intracellular integrin trafficking. We showed that RhoB regulates the vesicular transport of the integrin LFA-1 along the microtubule network in migrating T lymphocytes. Impairment in RhoB function resulted in the accumulation of both LFA-1 and the recycling endosomal marker Rab11 at the rear of migrating T lymphocytes and decreased the association between these molecules...
December 12, 2017: Science Signaling
Pontus Nordenfelt, Travis I Moore, Shalin B Mehta, Joseph Mathew Kalappurakkal, Vinay Swaminathan, Nobuyasu Koga, Talley J Lambert, David Baker, Jennifer C Waters, Rudolf Oldenbourg, Tomomi Tani, Satyajit Mayor, Clare M Waterman, Timothy A Springer
Integrin αβ heterodimer cell surface receptors mediate adhesive interactions that provide traction for cell migration. Here, we test whether the integrin, when engaged to an extracellular ligand and the cytoskeleton, adopts a specific orientation dictated by the direction of actin flow on the surface of migrating cells. We insert GFP into the rigid, ligand-binding head of the integrin, model with Rosetta the orientation of GFP and its transition dipole relative to the integrin head, and measure orientation with fluorescence polarization microscopy...
December 11, 2017: Nature Communications
Aitor Benedicto, Joana Marquez, Alba Herrero, Elvira Olaso, Elzbieta Kolaczkowska, Beatriz Arteta
BACKGROUND: Lymphocyte Function-Associated Antigen-1 (LFA-1; CD18/CD11a) is one of the main adhesion molecules used by immune cells to infiltrate the liver under inflammatory conditions. Recently, the expression of this integrin has also been reported on several solid tumors, including colorectal cancer. However, its functional role in the metastatic progression to the liver remains unknown. Using in vitro assays and an experimental orthotopic in vivo model of liver metastasis, we aimed to elucidate the role of tumor LFA-1 in the metastatic progression by means of the partial depletion of the β2 subunit of LFA-1, required for integrin activation, firm adhesion and signaling...
December 6, 2017: BMC Cancer
Alexander Buffone, Nicholas R Anderson, Daniel A Hammer
The recruitment of immune cells during inflammation is regulated by a multi-step cascade of cell rolling, activation, adhesion and transmigration through the endothelial barrier. Similarly, hematopoietic stem and progenitor cells (HSPCs) use this pathway to migrate and home to the bone marrow. After selectin-mediated braking, HSPCs migrate on adhesion ligands presented by the vascular endothelium including ICAM-1, VCAM-1 or MAdCAM-1. Here, we report that both the KG1a stem cell line and primary bone marrow CD34+ HSPCs can migrate against the direction of fluid flow on surfaces coated with cell adhesion molecules (CAMs), a behavior thus far only reported in T lymphocytes...
January 10, 2018: Journal of Cell Science
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