Gijs Kooij

University of Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (34)161.52 Total impact

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    ABSTRACT: Human brain microvascular endothelial cells forming the blood-brain barrier (BBB) release soluble vascular cell adhesion molecule-1 (sVCAM-1) under inflammatory conditions. Furthermore, sVCAM-1 serum levels in untreated patients with multiple sclerosis (MS) correlate with a breakdown of the BBB as measured by gadolinium-enhanced MRI. To date, it is unknown whether sVCAM-1 itself modulates BBB permeability. Here, we provide evidence that human brain endothelium expresses integrin α-4/β-1, the molecular binding partner of sVCAM-1, and that sVCAM-1 directly impairs BBB function by inducing intracellular signalling events through integrin α-4. Primary human brain microvascular endothelial cells showed low to moderate integrin α-4 and strong β-1 but no definite β-7 expression in vitro and in situ. Increased brain endothelial integrin α-4 expression was observed in active MS lesions in situ and after angiogenic stimulation in vitro. Exposure of cultured primary brain endothelial cells to recombinant sVCAM-1 significantly increased their permeability to the soluble tracer dextran, which was paralleled by formation of actin stress fibres and reduced staining of tight junction-associated molecules. Soluble VCAM-1 was also found to activate Rho GTPase and p38 MAP kinase. Chemical inhibition of these signalling pathways partially prevented sVCAM-1-induced changes of tight junction arrangement. Importantly, natalizumab, a neutralising recombinant monoclonal antibody against integrin α-4 approved for the treatment of patients with relapsing-remitting MS, partially antagonised the barrier-disturbing effect of sVCAM-1. In summary, we newly characterised sVCAM-1 as a compromising factor of brain endothelial barrier function that may be partially blocked by the MS therapeutic natalizumab.
    Acta Neuropathologica 03/2015; 129(5). DOI:10.1007/s00401-015-1417-0 · 9.78 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood-brain barrier (BBB). This study describes the effect of GM-CSF on human monocytes, macrophages and microglia. Furthermore, the expression of GM-CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM-CSF enhances monocyte migration across human BBB endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM-CSF is highly expressed by microglia and macrophages in MS lesions. The GM-CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM-CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM-CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 03/2015; DOI:10.1002/eji.201444960 · 4.52 Impact Factor
  • Gijs Kooij, Helga E de Vries
    Multiple Sclerosis 02/2015; 21(4). DOI:10.1177/1352458515573095 · 4.86 Impact Factor
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    ABSTRACT: Recent clinical trials in patients with inflammatory diseases like multiple sclerosis (MS) or inflammatory bowel disease (IBD) have shown the beneficial effects of probiotic helminth administration, although the underlying mechanism of action remains largely unknown. Potential cellular targets may include innate immune cells that propagate inflammation in these diseases, like pro-inflammatory macrophages. We here investigated the effects of the helminth Trichuris suis soluble products (SPs) on the phenotype and function of human inflammatory (granulocyte-macrophage colony-stimulating factor (GM-CSF)-differentiated) macrophages. Interestingly, we here show that T. suis SPs potently skew inflammatory macrophages into a more anti-inflammatory state in a Toll-like receptor 4 (TLR4)-dependent manner, and less effects are seen when stimulating macrophages with TLR2 or -3 ligands. Gene microarray analysis of GM-CSF-differentiated macrophages further revealed that many TLR4-induced inflammatory mediators, including interleukin (IL)-12B, CCL1 and CXCL9, are downregulated by T. suis SPs. In particular, we observed a strong reduction in the expression and function of P2RX7, a purinergic receptor involved in macrophage inflammation, leading to reduced IL-1β secretion. In conclusion, we show that T. suis SPs suppress a broad range of inflammatory pathways in GM-CSF-differentiated macrophages in a TLR4-dependent manner, thereby providing enhanced mechanistic insight into the therapeutic potential of this helminth for patients with inflammatory diseases.Genes and Immunity advance online publication, 10 July 2014; doi:10.1038/gene.2014.38.
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    ABSTRACT: Upregulation of intercellular adhesion molecule 1 (ICAM-1) is an early event in lesion formation in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Monitoring its expression may provide a biomarker for early disease activity and allow validation of anti-inflammatory interventions. Our objective was therefore to explore whether ICAM-1 expression can be visualized in vivo during EAE with magnetic resonance imaging (MRI) using micron-sized particles of iron oxide (MPIO), and to compare accumulation profiles of targeted and untargeted MPIO, and a gadolinium-containing agent. Targeted αICAM-1-MPIO/untargeted IgG-MPIO were injected at two model-characteristic phases of EAE (in myelin oligodendrocyte glycoprotein35–55-immunized C57BL/6 J mice), that is, at the peak of the acute phase (14 ± 1 days post-immunization) and during the chronic phase (26 ± 1 days post-immunization), followed by T2*-weighted MRI. Blood–brain barrier (BBB) permeability was measured using gadobutrol-enhanced MRI. Cerebellar microvessels were analyzed for ICAM-1 mRNA expression using quantitative PCR (qPCR). ICAM-1 and iron oxide presence was examined with immunohistochemistry (IHC). During EAE, ICAM-1 was expressed by brain endothelial cells, macrophages and T-cells as shown with qPCR and (fluorescent) IHC. EAE animals injected with αICAM-1-MPIO showed MRI hypointensities, particularly in the subarachnoid space. αICAM-1-MPIO presence did not differ between the phases of EAE and was not associated with BBB dysfunction. αICAM-1-MPIO were associated with endothelial cells or cells located at the luminal side of blood vessels. In conclusion, ICAM-1 expression can be visualized with in vivo molecular MRI during EAE, and provides an early tracer of disease activity. Copyright © 2014 John Wiley & Sons, Ltd.
    Contrast Media & Molecular Imaging 04/2014; 10(2). DOI:10.1002/cmmi.1602 · 3.33 Impact Factor
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    ABSTRACT: The trafficking of cytotoxic CD8(+) T lymphocytes across the lining of the cerebral vasculature is key to the onset of the chronic neuro-inflammatory disorder multiple sclerosis. However, the mechanisms controlling their final transmigration across the brain endothelium remain unknown. Here, we describe that CD8(+) T lymphocyte trafficking into the brain is dependent on the activity of the brain endothelial adenosine triphosphate-binding cassette transporter P-glycoprotein. Silencing P-glycoprotein activity selectively reduced the trafficking of CD8(+) T cells across the brain endothelium in vitro as well as in vivo. In response to formation of the T cell-endothelial synapse, P-glycoprotein was found to regulate secretion of endothelial (C-C motif) ligand 2 (CCL2), a chemokine that mediates CD8(+) T cell migration in vitro. Notably, CCL2 levels were significantly enhanced in microvessels isolated from human multiple sclerosis lesions in comparison with non-neurological controls. Endothelial cell-specific elimination of CCL2 in mice subjected to experimental autoimmune encephalomyelitis also significantly diminished the accumulation of CD8(+) T cells compared to wild-type animals. Collectively, these results highlight a novel (patho)physiological role for P-glycoprotein in CD8(+) T cell trafficking into the central nervous system during neuro-inflammation and illustrate CCL2 secretion as a potential link in this mechanism.
    Acta Neuropathologica 01/2014; DOI:10.1007/s00401-014-1244-8 · 9.78 Impact Factor
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    ABSTRACT: The purpose of this study was the generation of central nervous system (CNS)-excluded cannabinoid receptor agonists to test the hypothesis that inhibition of spasticity, due to CNS autoimmunity, could be controlled by affecting neurotransmission within the periphery. Procedures included identification of chemicals and modeling to predict the mode of exclusion; induction and control of spasticity in the ABH mouse model of multiple sclerosis; conditional deletion of CB1 receptor in peripheral nerves; side-effect profiling to demonstrate the mechanism of CNS-exclusion via drug pumps; genome-wide association study in N2(129×ABH) backcross to map polymorphic cannabinoid drug pump; and sequencing and detection of cannabinoid drug-pump activity in human brain endothelial cell lines. Three drugs (CT3, SAB378 and SAD448) were identified that control spasticity via action on the peripheral nerve CB1 receptor. These were peripherally restricted via drug pumps that limit the CNS side effects (hypothermia) of cannabinoids to increase the therapeutic window. A cannabinoid drug pump is polymorphic and functionally lacking in many laboratory (C57BL/6, 129, CD-1) mice used for transgenesis, pharmacology, and toxicology studies. This phenotype was mapped and controlled by 1-3 genetic loci. ABCC1 within a cluster showing linkage is a cannabinoid CNS-drug pump. Global and conditional CB1 receptor-knockout mice were used as controls. In summary, CNS-excluded CB1 receptor agonists are a novel class of therapeutic agent for spasticity.-Pryce, G., Visintin, C., Ramagopalan, S. V., Al-Izki, S., De Faveri, L. E., Nuamah, R. A., Mein, C. A., Montpetit, A., Hardcastle, A. J., Kooij, G., de Vries, H. E., Amor, S., Thomas, S. A., Ledent, C., Marsicano, G., Lutz, B., Thompson, A. J., Selwood, D. L., Giovannoni, G., Baker, D. Control of spasticity in a multiple sclerosis model using central nervous system-excluded CB1 cannabinoid receptor agonists.
    The FASEB Journal 01/2014; 28(1):117-130. DOI:10.1096/fj.13-239442 · 5.48 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder, which is marked by the invasion of the central nervous system by monocyte-derived macrophages and autoreactive T cells across the brain vasculature. Data from experimental animal models recently implied that the passage of leukocytes across the brain vasculature is preceded by their traversal across the blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus. The correlation between the presence of leukocytes in the CSF of patients suffering from MS and the number of inflammatory lesions as detected by magnetic resonance imaging suggests that inflammation at the choroid plexus contributes to the disease, although in a yet unknown fashion. We here provide first insights into the involvement of the choroid plexus in the onset and severity of the disease and in particular address the role of the tight junction protein claudin-3 (CLDN3) in this process. Detailed analysis of human post-mortem brain tissue revealed a selective loss of CLDN3 at the choroid plexus in MS patients compared to control tissues. Importantly, mice that lack CLDN3 have an impaired BCSFB and experience a more rapid onset and exacerbated clinical signs of experimental autoimmune encephalomyelitis, which coincides with enhanced levels of infiltrated leukocytes in their CSF. Together, this study highlights a profound role for the choroid plexus in the pathogenesis of multiple sclerosis, and implies that CLDN3 may be regarded as a crucial and novel determinant of BCSFB integrity.
    Acta Neuropathologica 12/2013; DOI:10.1007/s00401-013-1227-1 · 9.78 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and marked by deposition of amyloid-β (Aβ) within the brain. Alterations of Aβ transporters at the neurovasculature may play a role in the disease process. We investigated the expression of ABC transporters P-glycoprotein (P-gp) and breast cancer related protein (BCRP) in non-neurologic controls, AD, and severe capillary cerebral amyloid angiopathy (capCAA) cases, which are characterized by deposition of Aβ within cerebral capillaries. Our data show that microvascular expression of P-gp and BCRP is strikingly decreased in capCAA-affected vessels but not in AD and control samples. Messenger RNA levels of P-gp, but not of BCRP, were downregulated in brain endothelial cells on exposure to oligomeric Aβ42, but not fibrillar Aβ42 or Aβ40. Coincubating Aβ42 together with clusterin, an amyloid-associated protein highly expressed in capCAA-affected vessels, strongly reduced levels of P-gp. In conclusion, accumulation of Aβ, in combination with clusterin, within and around cerebral capillaries, may further aggravate the disease process in AD by affecting P-gp expression. Loss of P-gp expression or activity may serve as a selective biomarker for ongoing capCAA.
    Neurobiology of aging 10/2013; 35(3). DOI:10.1016/j.neurobiolaging.2013.09.015 · 4.85 Impact Factor
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    ABSTRACT: Blood-brain barrier (BBB) dysfunction is a major hallmark of many neurological diseases, including multiple sclerosis (MS). Using a genomics approach, we defined a microRNA signature that is diminished at the BBB of MS patients. In particular, miR-125a-5p is a key regulator of brain endothelial tightness and immune cell efflux. Our findings suggest that repair of a disturbed BBB through microRNAs may represent a novel avenue for effective treatment of MS.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2013; 33(16):6857-6863. DOI:10.1523/JNEUROSCI.3965-12.2013 · 6.75 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) show great therapeutic potential for the treatment of various immune mediated diseases, including Multiple Sclerosis (MS). Systemic administration of MSCs during experimental allergic encephalomyelitis (EAE), an animal model for MS, was shown to reduce the infiltration of T cells, B cells, and macrophages into the CNS. Whether endogenous MSCs are mobilized and potentially modulate the severity of disease is not known. Here we show that during the acute phase of EAE, MSCs numbers in the bone marrow were severely reduced, which restored to control levels during the progressive phase of the disease. The number of bone marrow MSCs inversely correlated with the number of both CD4 and CD8 T cells present in the bone marrow indicating a link between activated T cells and MSC mobilization. Analysis of CD70-transgenic mice, which have a constitutively activated immune system and elevated number of activated T cells in the bone marrow, showed severely reduced number of bone marrow MSCs. Transfer of T cells that were activated through their CD27 receptor reduced the number of bone marrow MSCs dependent on IFN-y. These data provide a mechanism by which MSCs can be mobilized from the bone marrow in order to contribute to tissue repair at a distant location.
    Frontiers in Immunology 03/2013; 4:49. DOI:10.3389/fimmu.2013.00049
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    ABSTRACT: Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood–brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer’s disease and address potential underlying mechanisms.
    Epilepsia 11/2012; 53(s6). DOI:10.1111/j.1528-1167.2012.03702.x · 4.58 Impact Factor
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    ABSTRACT: Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya(®)) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-α treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-α treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration.
    Acta Neuropathologica 07/2012; 124(3):397-410. DOI:10.1007/s00401-012-1014-4 · 9.78 Impact Factor
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    ABSTRACT: Neuroinflammation contributes to a wide range of disorders of the central nervous system (CNS). Of the available anti-inflammatory drugs, only glucocorticoids have shown central efficacy in CNS-related disorders, such as multiple sclerosis (MS). However, their side effects are dose limiting. To optimally improve the therapeutic window of methylprednisolone, we enhanced its CNS delivery by using pegylated liposomes conjugated to the brain-targeting ligand glutathione. In healthy rats, plasma circulation and brain uptake were significantly increased after encapsulating methylprednisolone in glutathione pegylated (GSH-PEG) liposomes. Furthermore, the efficacy of GSH-PEG liposomal methylprednisolone was investigated in rats with acute experimental autoimmune encephalomyelitis (EAE), an animal model of MS; rats received treatment (10mg/kg; i.v. injection), before disease onset, at disease onset, or at the peak of disease. Free methylprednisolone and non-targeted pegylated (PEG) liposomal methylprednisolone served as control treatments. When treatment was initiated at disease onset, free methylprednisolone showed no effect, while GSH-PEG liposomal methylprednisolone significantly reduced the clinical signs to 42±6.4% of saline control. Moreover, treatment using GSH-PEG liposomes was significantly more effective compared to PEG liposomes. Our findings hold promise for MS treatment and warrant further investigations into this brain delivery system for the treatment of neuroinflammation.
    Journal of Controlled Release 06/2012; 164(3). DOI:10.1016/j.jconrel.2012.06.022 · 7.26 Impact Factor
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    ABSTRACT: The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya®) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood-brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P5 largely contributes to the maintenance of brain endothelial barrier function. We analyzed the expression of S1P5 in human post-mortem tissues using immunohistochemistry. The function of S1P5 at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus-mediated knockdown of S1P5. Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. We show that activation of S1P5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro. These results were corroborated by genetically silencing S1P5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Our findings demonstrate that S1P5 in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium.
    Journal of Neuroinflammation 06/2012; 9:133. DOI:10.1186/1742-2094-9-133 · 4.90 Impact Factor
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    ABSTRACT: ATP-binding cassette (ABC) transporters are highly expressed by brain endothelial cells that form the blood-brain barrier (BBB). These efflux pumps play an important role in maintaining brain homeostasis as they actively hinder the entry of unwanted blood-derived compounds into the central nervous system (CNS). Consequently, their high activity at the BBB has been a major hurdle for the treatment of several brain diseases, as they prevent numerous drugs to reach their site of action within the brain. Importantly, recent data indicate that endogenous substrates for ABC transporters may include inflammatory mediators, such as prostaglandins, leukotrienes, cytokines, chemokines, and bioactive lipids, suggesting a potential role for ABC transporters in immunological responses, and more specifically in inflammatory brain disorders, such as multiple sclerosis (MS). In this review, we will give a comprehensive overview of recent findings that illustrate this novel role for ABC transporters in neuro-inflammatory processes. Moreover, we will provide first insights into underlying mechanisms and focus on the importance for bioactive lipids, in particular platelet-activating factor, herein. A thorough understanding of these events may form the basis for the development for selective treatment modalities to dampen the neuro-inflammatory attack in MS and thereby reducing tissue damage.
    Frontiers in Pharmacology 04/2012; 3:74. DOI:10.3389/fphar.2012.00074

Publication Stats

542 Citations
161.52 Total Impact Points

Institutions

  • 2014
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2007–2014
    • VU University Medical Center
      • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands
  • 2009–2013
    • VU University Amsterdam
      • Department of Molecular Cell Biology and Immunology
      Amsterdamo, North Holland, Netherlands