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diapedesis + lymphocyte

Ibrahim M Sektioglu, Rafael Carretero, Noemi Bender, Christian Bogdan, Natalio Garbi, Viktor Umansky, Ludmila Umansky, Katharina Urban, Magnus von Knebel-Döberitz, Veena Somasundaram, David Wink, Philipp Beckhove, Günter J Hämmerling
In tumor biology, nitric oxide (NO) is generally regarded as an immunosuppressive molecule that impedes T-cell functions and activation of endothelial cells. Contrasting with this view, we here describe a critical role for NO derived from inducible nitric oxide (iNOS)-expressing tumor macrophages in T-cell infiltration and tumor rejection as shown by iNOS gene deletion, inhibition of iNOS, or NO donors. Specifically, macrophage-derived NO was found to induce on tumor vessels adhesion molecules that were required for T-cell extravasation...
2016: Oncoimmunology
Ryan C Winger, Christopher T Harp, Ming-Yi Chiang, David P Sullivan, Richard L Watson, Evan W Weber, Joseph R Podojil, Stephen D Miller, William A Muller
Leukocyte trafficking into the CNS is a prominent feature driving the immunopathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. We report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood-brain barrier model...
February 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Luca G Guidotti, Donato Inverso, Laura Sironi, Pietro Di Lucia, Jessica Fioravanti, Lucia Ganzer, Amleto Fiocchi, Maurizio Vacca, Roberto Aiolfi, Stefano Sammicheli, Marta Mainetti, Tiziana Cataudella, Andrea Raimondi, Gloria Gonzalez-Aseguinolaza, Ulrike Protzer, Zaverio M Ruggeri, Francis V Chisari, Masanori Isogawa, Giovanni Sitia, Matteo Iannacone
Effector CD8(+) T cells (CD8 TE) play a key role during hepatotropic viral infections. Here, we used advanced imaging in mouse models of hepatitis B virus (HBV) pathogenesis to understand the mechanisms whereby these cells home to the liver, recognize antigens, and deploy effector functions. We show that circulating CD8 TE arrest within liver sinusoids by docking onto platelets previously adhered to sinusoidal hyaluronan via CD44. After the initial arrest, CD8 TE actively crawl along liver sinusoids and probe sub-sinusoidal hepatocytes for the presence of antigens by extending cytoplasmic protrusions through endothelial fenestrae...
April 23, 2015: Cell
Liat Stoler-Barak, Ekaterina Petrovich, Tegest Aychek, Irina Gurevich, Orna Tal, Miki Hatzav, Neta Ilan, Sara W Feigelson, Guy Shakhar, Israel Vlodavsky, Ronen Alon
Heparanase, the exclusive mammalian heparan sulfate-degrading enzyme, has been suggested to be utilized by leukocytes to penetrate through the dense basement membranes surrounding blood venules. Despite its established role in tumor cell invasion, heparanase function in leukocyte extravasation has never been demonstrated. We found that TH1/TC1-type effector T cells are highly enriched for this enzyme, with a 3.6-fold higher heparanase mRNA expression compared with naive lymphocytes. Using adoptive transfer of wild-type and heparanase-deficient effector T cells into inflamed mice, we show that T-cell heparanase was not required for extravasation inside inflamed lymph nodes or skin...
May 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Yanping Huang, Fiona Clarke, Mobin Karimi, Nathan H Roy, Edward K Williamson, Mariko Okumura, Kazuhiro Mochizuki, Emily J H Chen, Tae-Ju Park, Gudrun F Debes, Yi Zhang, Tom Curran, Taku Kambayashi, Janis K Burkhardt
Effector T cell migration into inflamed sites greatly exacerbates tissue destruction and disease severity in inflammatory diseases, including graft-versus-host disease (GVHD). T cell migration into such sites depends heavily on regulated adhesion and migration, but the signaling pathways that coordinate these functions downstream of chemokine receptors are largely unknown. Using conditional knockout mice, we found that T cells lacking the adaptor proteins CRK and CRK-like (CRKL) exhibit reduced integrin-dependent adhesion, chemotaxis, and diapedesis...
March 2, 2015: Journal of Clinical Investigation
Michael Abadier, Neda Haghayegh Jahromi, Ludmila Cardoso Alves, Rémy Boscacci, Dietmar Vestweber, Scott Barnum, Urban Deutsch, Britta Engelhardt, Ruth Lyck
The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow...
April 2015: European Journal of Immunology
Monica D Prakash, Marcia A Munoz, Rohit Jain, Philip L Tong, Aulikki Koskinen, Matthias Regner, Oded Kleifeld, Bosco Ho, Matthew Olson, Stephen J Turner, Paulus Mrass, Wolfgang Weninger, Phillip I Bird
Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently...
December 18, 2014: Immunity
Peter Friedl, Bettina Weigelin
Granzyme B released by leukocytes cleaves multiple intracellular substrates required for target cell lysis. In this issue of Immunity, Prakash et al. (2014) demonstrate that granzyme B cleaves basement membrane proteins and promotes cytotoxic T cell diapedesis into inflamed tissue.
December 18, 2014: Immunity
Abha Kaistha, Jeremiah Levine
Inflammatory bowel disease (IBD) is an idiopathic disease thought to be caused by a dysregulated immune response to host intestinal microflora. The role of genetic factors is indicated by familial clustering of cases and higher incidence in monozygotic twins. An interaction between genetic and environmental factors is thought to play a role in the pathogenesis of these disorders. Changes in diet, antibiotic use and intestinal colonization have likely contributed to increased prevalence of inflammatory bowel disease in the past century...
December 2014: Current Problems in Pediatric and Adolescent Health Care
Roberta Martinelli, Adam S Zeiger, Matthew Whitfield, Tracey E Sciuto, Ann Dvorak, Krystyn J Van Vliet, John Greenwood, Christopher V Carman
Immune cell trafficking requires the frequent breaching of the endothelial barrier either directly through individual cells ('transcellular' route) or through the inter-endothelial junctions ('paracellular' route). What determines the loci or route of breaching events is an open question with important implications for overall barrier regulation. We hypothesized that basic biomechanical properties of the endothelium might serve as crucial determinants of this process. By altering junctional integrity, cytoskeletal morphology and, consequently, local endothelial cell stiffness of different vascular beds, we could modify the preferred route of diapedesis...
September 1, 2014: Journal of Cell Science
Verena Küppers, Dietmar Vestweber, Dörte Schulte
The passage of leukocytes across the blood vessel wall is a fundamental event in the inflammatory response. During the last decades, there has been significant progress in understanding the molecular mechanisms involved in leukocyte transmigration. However, it is still a matter of debate whether leukocytes migrate paracellularly or transcellularly through an endothelial cell layer. We could recently show that a VE-cadherin-α-catenin fusion protein locks endothelial junctions in the skin and strongly reduces leukocyte diapedesis in lung, skin and cremaster, establishing the paracellular route as the major transmigration pathway in these tissues...
January 1, 2013: Tissue Barriers
Jin Hee Kang, Seung Rim Hwang, Shijin Sung, Ji Ae Jang, Md Mahmudul Alam, Keum Hee Sa, Sang-Yeob Kim, In San Kim, Young Ro Byun, Young Mo Kang
Heparin has a potential regulatory role in inflammatory diseases. However, the anticoagulant activity and poor oral bioavailability of heparin limit its use as an anti-inflammatory agent. Conjugation of bis-deoxycholic acid to 6-O-desulfated low molecular weight heparin (6DSHbD) was efficiently internalized by activated endothelial cells via a 2-step model, in which heparin attaches to adhesion molecules that facilitate accessibility of the bile acid conjugate to membrane transporters. The critical role of P-selectin during endothelial cell uptake of 6DSHbD by arthritic tissue was confirmed in p-selectin(-/-) arthritic mice...
June 10, 2014: Journal of Controlled Release: Official Journal of the Controlled Release Society
Nancy L Monson, Sterling B Ortega, Sara J Ireland, Anouk Jm Meeuwissen, Ding Chen, Erik J Plautz, Erin Shubel, Xiangmei Kong, Min K Li, Laura H Freriks, Ann M Stowe
BACKGROUND: Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset...
2014: Journal of Neuroinflammation
Liat Stoler-Barak, Sagi Barzilai, Ayelet Zauberman, Ronen Alon
Leukocyte diapedesis is a chemotactic multistep process that requires optimal chemoattractant presentation by the endothelial barrier. Recent studies have described a critical role for heparan sulfate glycosaminoglycans (HSGAGs) in the presentation and functions of chemokines essential for lymphocyte interactions with the lymph node vasculature. We wished to test whether HS expression by a prototypic endothelial cell type, i.e. human umbilical vein endothelial cells (HUVECs), is critical for their ability to support neutrophil and lymphocyte adhesion and transendothelial migration (TEM) under shear flow...
June 2014: International Immunology
Roser Gorina, Ruth Lyck, Dietmar Vestweber, Britta Engelhardt
In acute neuroinflammatory states such as meningitis, neutrophils cross the blood-brain barrier (BBB) and contribute to pathological alterations of cerebral function. The mechanisms that govern neutrophil migration across the BBB are ill defined. Using live-cell imaging, we show that LPS-stimulated BBB endothelium supports neutrophil arrest, crawling, and diapedesis under physiological flow in vitro. Investigating the interactions of neutrophils from wild-type, CD11a(-/-), CD11b(-/-), and CD18(null) mice with wild-type, junctional adhesion molecule-A(-/-), ICAM-1(null), ICAM-2(-/-), or ICAM-1(null)/ICAM-2(-/-) primary mouse brain microvascular endothelial cells, we demonstrate that neutrophil arrest, polarization, and crawling required G-protein-coupled receptor-dependent activation of β2 integrins and binding to endothelial ICAM-1...
January 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Elisabeth Devilard, Luc Xerri, Patrice Dubreuil, Marc Lopez, Nicolas Reymond
Lymphocyte trafficking and migration through vascular endothelial cells (ECs) in secondary lymphoid tissues is critical for immune protection. In the present study, we investigate the role of nectin cell adhesion molecules for the migration of lymphocytes through ECs. Nectins are key players for the establishment of homotypic and heterotypic cell to cell contacts; they are required for cell to cell adherens junction formation and take part in the transendothelial migration of monocytes during the step of diapedesis, when monocytes migrate through EC junctions...
2013: PloS One
Jordan Jacobelli, Miriam Estin Matthews, Stephanie Chen, Matthew F Krummel
Following activation, T cells are released from lymph nodes to traffic via the blood to effector sites. The re-entry of these activated T cells into tissues represents a critical step for them to carry out local effector functions. Here we have assessed defects in effector T cells that are acutely depleted in Myosin-IIA (MyoIIA) and show a T cell intrinsic requirement for this motor to facilitate the diapedesis step of extravasation. We show that MyoIIA accumulates at the rear of T cells undergoing trans-endothelial migration...
2013: PloS One
Roberta Martinelli, Gail Newton, Christopher V Carman, John Greenwood, Francis W Luscinskas
OBJECTIVE: Although endothelial CD47, a member of the immunoglobulin superfamily, has been implicated in leukocyte diapedesis, its capacity for intracellular signaling and physical localization during this process has not been addressed in detail. This study examined endothelial CD47 spatiotemporal behavior and signaling pathways involved in regulating T-cell transendothelial migration. APPROACH AND RESULTS: By biochemical methods, transmigration assays, and live-cell microscopy techniques, we show that endothelial CD47 engagement results in intracellular calcium mobilization, increased permeability, and activation of Src and AKT1/phosphoinositide 3-kinase in brain microvascular endothelial cells...
November 2013: Arteriosclerosis, Thrombosis, and Vascular Biology
Shmuel J Cohen, Irina Gurevich, Sara W Feigelson, Ekaterina Petrovich, Markus Moser, Guy Shakhar, Reinhard Fassler, Ronen Alon
Kindlin-3 is an integrin-binding focal adhesion adaptor absent in patients with leukocyte and platelet adhesion deficiency syndrome and is critical for firm integrin-dependent leukocyte adhesion. The role of this adaptor in leukocyte diapedesis has never been investigated. In the present study, the functions of Kindlin-3 in this process were investigated in effector T lymphocytes trafficking to various lymphoid and nonlymphoid tissues. In vitro, Kindlin-3-deficient T cells displayed severely impaired lymphocyte function antigen-1-dependent lymphocyte adhesion but partially conserved very late antigen-4 adhesiveness...
October 10, 2013: Blood
Daniel A Belkin, Hiroshi Mitsui, Claire Q F Wang, Juana Gonzalez, Shali Zhang, Kejal R Shah, Israel Coats, Mayte Suàrez-Fariñas, James G Krueger, Diane Felsen, John A Carucci
OBJECTIVE: To characterize the presence of CD200 and CD200 receptor (CD200R) in the human cutaneous squamous cell carcinoma (SCC) microenvironment and to define a possible role for the CD200 axis in immune evasion by SCC. DESIGN: Gene expression in SCC vs normal skin was studied. Laser capture microdissection was used to determine differential expression of CD200 in normal skin vs actinic keratosis vs SCC in situ vs invasive SCC. Immunofluorescence microscopy was used to define expression of CD200R on macrophages, myeloid dendritic cells, natural killer cells, and T cells in SCC vs normal skin...
February 2013: JAMA Dermatology
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