Differential Roles for Endothelial ICAM-1, ICAM-2, and VCAM-1 in Shear-Resistant T Cell Arrest, Polarization, and Directed Crawling on Blood–Brain Barrier Endothelium

Steiner, Oliver; Coisne, Caroline; Cecchelli, Roméo; Boscacci, Rémy; Deutsch, Urban; Engelhardt, Britta; Lyck, Ruth

doi:10.4049/jimmunol.0903732

Cited by 233 publications

(364 citation statements)

References 37 publications

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“…T lymphocytes were allowed to accumulate on the endothelium at low shear stress (0.15 dyn/cm 2 ) and after the accumulation phase flow was increased to physiological shear stress (1.5 dyn/cm 2 ). TEM is initiated by capture of the T lymphocytes to the endothelium during the accumulation phase, followed by the acquisition of a polarized phenotype and an optional crawling step to find permissive sites for diapedesis (24). In contrast to previous studies that addressed effects of Nef on cell adhesion in the absence of physiological shear flow (8,14), WT or F195A Nef did not affect the initial accumulation of T cells on the CCL-21-coated endothelium under our shear-flow conditions (Fig.…”

Section: Hiv-1 Nef Interferes With T-lymphocyte Transmigration Under contrasting

confidence: 51%

“…Because transmigration across the endothelial cells lining HEVs constitutes a critical step in the homing process, we first addressed whether Nef affects crawling and diapedesis through an endothelial cell monolayer under shear flow (23,24). Transduced and purified T lymphocytes were differentially labeled with CellTracker dyes in vitro, mixed, and perfused over a CCL-21-coated primary brain microvascular endothelial cell monolayer to image the recruitment process by video microscopy over 50 min ( Fig.…”

Section: Hiv-1 Nef Interferes With T-lymphocyte Transmigration Under mentioning

confidence: 99%

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HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Stolp

Imle

Coelho

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef’s influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef’s ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.

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Section: Hiv-1 Nef Interferes With T-lymphocyte Transmigration Under contrasting

confidence: 51%

Section: Hiv-1 Nef Interferes With T-lymphocyte Transmigration Under mentioning

confidence: 99%

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Stolp

Imle

Coelho

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…2B), suggesting that other trafficking cues such as LFA-1/ICAM-1 interaction might maintain this reduced T-cell adhesion to the inflamed spinal cord microvascular wall [31].…”

Section: Lack Of T-cell Rolling Results In Reduced T-cell Adhesion Inmentioning

confidence: 99%

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

et al. 2014

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T-cell migration across the blood-brain barrier is a crucial step in the pathogenesis of EAE, an animal model for MS. Live cell imaging studies demonstrated that P-selectin glycoprotein ligand-1 (PSGL-1) and its endothelial ligands E-and P-selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL-1 or E/P-selectins does not result in ameliorated EAE, we speculated that T-cell entry into the spinal cord is independent of PSGL-1 and E/P-selectin. Performing intravital microscopy, we observed the interaction of WT or PSGL-1 −/− proteolipid protein-specific T cells in inflamed spinal cord microvessels of WT or E/P-selectin −/− SJL/J mice during EAE. T-cell rolling but not T-cell capture was completely abrogated in the absence of either PSGL-1 or E-and P-selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T-cell invasion into the CNS parenchyma. Thus, PSGL-1 interaction with E/P-selectin is essential for T-cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T-cell rolling is not required for successful T-cell entry into the CNS and initiation of EAE.Keywords: Blood-brain barrier r Experimental autoimmune encephalomyelitis r P-selectin r P-selectin glycoprotein ligand-1 r T-cell rolling Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIn MS, and in its animal model, EAE, neuro-Ag-specific CD4 + (where CD is cluster of differentiation) T cells breach the bloodbrain barrier (BBB) and gain access to the CNS, where they cause inflammation, demyelination, and BBB breakdown leading to the clinical manifestation of these diseases. T-cell migration across the BBB is a multi-step process mediated by the sequential interaction of different adhesion and/or signaling molecules on the T cells and Correspondence: Prof. Britta Engelhardt e-mail: bengel@tki.unibe.ch the highly specialized endothelium of the BBB [1]. The discovery that α4β1-integrin plays a critical role in T-cell trafficking across the BBB during EAE has led to the development of a humanized monoclonal anti-α4-integrin Ab (natalizumab) for the treatment of MS [2].In vivo live cell imaging studies have provided direct evidence that the multistep extravasation of encephalitogenic T cells across the spinal cord microvasculature during initiation of EAE is unique [3]. Initiation of T-cell interaction with the spinal cord microvascular endothelium takes place in the absence of rolling and is rather mediated by α4-integrin-mediated G-protein-independent capture and subsequent G-protein-dependent arrest of the T cells in spinal cord microvessels [3]. Once neuroinflammation iswww.eji-journal.eu 2288 Karthik Sathiyanadan et al. Eur. J. Immunol. 2014. 44: 2287-2294 ongoing, it is mostly T-cell rolling with a few alternative capture events also detected, which characterize th...

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“…Cav-1 levels are known to increase during BBB breakdown following ischemic stroke, when enhanced transcytosis initiates BBB dysfunction (24,25). Finally, healthy BBB vasculature has low levels of leukocyte adhesion molecules, such as vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecules (ICAMs)-1 and -2, which are up-regulated on CNS vessels during EAE/MS to promote T-cell trafficking into the parenchyma (26)(27)(28)(29). Blockade of VCAM-1 interactions with its cognate lymphocyte ligand integrin α4 reduces the clinical severity of EAE (30) and is the basis for MS-modifying therapy with natalizumab (31).…”

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confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

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Differential Roles for Endothelial ICAM-1, ICAM-2, and VCAM-1 in Shear-Resistant T Cell Arrest, Polarization, and Directed Crawling on Blood–Brain Barrier Endothelium

Cited by 233 publications

References 37 publications

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

PSGL‐1 and E/P‐selectins are essential for T‐cell rolling in inflamed CNS microvessels but dispensable for initiation of EAE

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

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