E- and P-Selectin Are Not Involved in the Recruitment of Inflammatory Cells Across the Blood-Brain Barrier in Experimental Autoimmune Encephalomyelitis

Engelhardt, Britta; Vestweber, Dietmar; Schulz, M

doi:10.1182/blood.v90.11.4459.4459_4459_4472

Cited by 44 publications

(43 citation statements)

References 41 publications

(10 reference statements)

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“…Establishment and culture of the CD4 + MHC class II‐restricted proteolipid protein (PLP)‐specific T cell lines derived from SJL/N mice and induction of active EAE (aEAE) and T cell tEAE have all been described in great detail before 37, 39, 40. G i ‐protein mediated signals in encephalitogenic T lymphoblasts were blockedby incubation in vitro with PTX or MTX (100 ng/ml) for 2 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemistry was performed on frozen brain sections exactly as described 40 using a three‐step immunoperoxidase technique for goat IgG (Vector, Linaris Biologische Produkte, Wertheim, Germany). Each batch of anti‐chemokine antibodies needed to be carefully tested for optimal concentration in immunostaining and antibodies were used from 10 to 20 μg/ml.…”

Section: Methodsmentioning

confidence: 99%

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Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

2002

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Migration of autoaggressive T cells across the blood‐brain barrier (BBB) is critically involved in the initiation of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. The direct involvement of chemokines in this process was suggested by our recent observation that G‐protein‐mediated signaling is required to promote adhesion strengthening of encephalitogenic T cells on BBB endothelium in vivo. To search for chemokines present at the BBB, we performed in situ hybridizations and immunohistochemistry and found expression of the lymphoid chemokines CCL19/ELC and CCL21/SLC in venules surrounded by inflammatory cells. Their expression was paralleled by the presence of their common receptor CCR7 in inflammatory cells in brain and spinal cord sections of mice afflicted with EAE. Encephalitogenic T cells showed surface expression of CCR7 and the alternative receptor for CCL21, CXCR3. They specifically chemotaxed towards both CCL19 or CCL21 in a concentration dependent and pertussis toxin‐sensitive manner comparable to naive lymphocytes in vitro. Binding assays on frozen sections of EAE brains demonstrated a functional involvement of CCL19 and CCL21 in adhesion strengthening of encephalitogenic T lymphocytes to inflamed venules in the brain. Taken together our data suggest that the lymphoid chemokines CCL19 and CCL21 besides regulating lymphocyte homing to secondary lymphoid tissue are involved in T lymphocyte migration into the immunoprivileged central nervous system during immunosurveillance and chronic inflammation.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

2002

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“…Immunohistochemistry was performed on frozen sections of brains and spinal cords exactly as previously described 34. Briefly, cryostat sections were air‐dried overnight, acetone‐fixed and stained using a three‐step immunoperoxidase technique (Vector, Linaris Biologische Produkte, Wertheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

Encephalitogenic T?cells use LFA-1 for transendothelial migration but not during capture and initial adhesion strengthening in healthy spinal cord microvesselsin vivo

Laschinger

Vajkoczy

Engelhardt³

2002

Eur. J. Immunol.

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LFA‐1 on the surface of encephalitogenic T cells has been suggested to be involved in the pathogenesis of experimental autoimmune encephalomyelitis. By applying a novel technique of intravitalfluorescence microscopy that enables us to visualize the interaction of circulating encephalitogenic T lymphoblasts within the healthy spinal cord white matter microvasculature in vivo, weinvestigated the possible involvement of LFA‐1 on circulating encephalitogenic T cells in their multi‐step interaction with the blood‐brain barrier endothelium in vivo. LFA‐1 was found to mediate neither the G‐protein‐independent capture nor the G‐protein‐dependent initial adhesion strengthening of encephalitogenic T cell blasts within spinal cord microvessels. In contrast, blocking of LFA‐1 on encephalitogenic T lymphoblasts resulted in a significantly reduced number of T cells firmly adhering within spinal cord microvessels 2 h after injection and in a significantly reduced number of T cells subsequently migrating across the vascular wall into the spinal cord parenchyme. Our study provides the first direct evidence that encephalitogenic T cells use LFA‐1 for transendothelial migration but not for capture and initial adhesion in spinal cord microvessels in vivo.

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“…Tethering, under shear forces of the flowing blood, is permissive for rolling and is facilitated by cytokine‐mediated endothelial activation. There is preliminary evidence for the role of selectins in leukocyte rolling on pial vessels of the brain, based on IVM experiments in mice with EAE (7, 18, 30, 32, 74). Rolling gives traveling leukocytes the opportunity to scan endothelial surfaces for luminal chemokines immobilized by association with glycosaminoglycans or other binding moieties (Figure 1).…”

Section: The Multistep Paradigm Of Leukocyte–endothelial Interactionsmentioning

confidence: 99%

“…This may be responsible for the low rates of leukocyte entry in the healthy brain. ICAM‐1 expression in brain microvascular endothelial cells was up‐regulated during EAE (30, 93) and MS (12).…”

Section: Leukocyte Integrins and Endothelial Cell‐adhesion Molecules:mentioning

confidence: 99%

Inflammatory Cell Migration into the Central Nervous System: A Few New Twists on an Old Tale

2007

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Understanding the mechanisms of leukocyte trafficking into the brain might provide insights into how to modulate pathologic immune responses or enhance host protective mechanisms in neuroinflammatory diseases such as multiple sclerosis. This review summarized our knowledge about the sites for leukocyte entry into the central nervous system, highlighting the routes from blood into the perivascular space and brain parenchyma through the blood-brain barrier. We further discussed the multistep paradigm of leukocyte-endothelial interactions at the blood-brain barrier, focusing on the adhesion molecules and chemokines involved in leukocyte transmigration. Luminal chemokines, which are immobilized on endothelial surfaces, initiate leukocyte integrin clustering and conformational change, leading to leukocyte arrest. Some leukocytes undergo post-arrest locomotion across the endothelial surface until interendothelial junctions are identified. Leukocytes then extend protrusions through the interendothelial junctions, in search of abluminal chemokines, which will serve as guidance cues for transmigration. Extravasating cells first accumulate in the perivascular space between the endothelial basement membrane and the basement membrane of the glia limitans. Matrix metalloproteases may be involved in leukocyte transverse across glia limitans into the brain parenchyma. The adhesion molecules and chemokine receptors provide attractive targets for neuroinflammatory diseases because of their important role in mediating central nervous system inflammation. Pathol 2007;17:243-250. The central nervous system (CNS) parenchyma is an immune-privileged organ, largely because it lacks resident dendritic cells, which are the cellular elements required for afferent communication to the immune system (34). Intraparenchymal immune-mediated inflammation reliably follows peripheral sensitization against a pathogen or autoantigen harbored within the CNS, illustrating efficient immune surveillance of the CNS and competent effector mechanisms. Once begun, immune-mediated CNS inflammation differs from that in peripheral tissues, in part because of the special character of the blood-brain barrier (BBB), which, along with factors produced by resident neuroepithelial cells, governs trafficking, survival and effector functions of hematogenous leukocytes during inflammatory states (1,28,69,79). Understanding how leukocytes migrate across the BBB has important implications. Recent clinical trials in relapsing-remitting multiple sclerosis (MS) using natalizumab, humanized antibodies directed against α 4 integrins, demonstrated efficacy (6). Understanding the mechanisms of leukocyte trafficking into the brain might provide insights into how to modulate pathologic immune responses or enhance host protective mechanisms in neuroinflammatory diseases (28). BrainLeukocyte entry into tissues is governed by the presence of chemokines and adhesion molecules at post-capillary venules (14,85,90,108). Compared with peripheral microvasculature, the molecular mechan...

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E- and P-Selectin Are Not Involved in the Recruitment of Inflammatory Cells Across the Blood-Brain Barrier in Experimental Autoimmune Encephalomyelitis

Cited by 44 publications

References 41 publications

Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis

Encephalitogenic T?cells use LFA-1 for transendothelial migration but not during capture and initial adhesion strengthening in healthy spinal cord microvesselsin vivo

Inflammatory Cell Migration into the Central Nervous System: A Few New Twists on an Old Tale

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