ORCID Profile
0000-0003-1714-2294
Current Organisations
KU Leuven
,
King Saud University
,
Katholieke Universiteit Leuven (KU Leuven)
,
Royal College of Physicians
,
Royal Academy of Medicine of Belgium
,
Belgian American Educational Foundation (BAEF)
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Publications
The Collagen Binding Domain of Gelatinase A Modulates Degradation of Collagen IV by Gelatinase B
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.JMB.2008.12.021
Abstract: Type IV collagen remodeling plays a critical role in inflammatory responses, angiogenesis and metastasis. Its remodeling is executed by a family of matrix metalloproteinases (MMPs), of which the constitutive gelatinase A (MMP2) and the inducible gelatinase B (MMP9) are key ex les. Thus, in many pathological conditions, both gelatinases act together. Kinetic data are reported for the enzymatic processing at 37 degrees C of type IV collagen from human placenta by MMP9 and its modulation by the fibronectin-like collagen binding domain (CBD) of MMP2. The alpha1 and alpha2 chain components of type IV collagen were cleaved by gelatinases and identified by mass spectrometry as well as Edman sequencing. Surface plasmon resonance interaction assays showed that CBD bound type IV collagen at two topologically distinct sites. On the basis of linked-function analysis, we demonstrated that CBD of MMP2 tuned the cleavage of collagen IV by MMP9, presumably by inducing a ligand-linked structural change on the type IV collagen. At low concentrations, the CBD bound the first site and thereby allosterically modulated the binding of MMP9 to collagen IV, thus enhancing the collagenolytic activity of MMP9. At high concentrations, CBD binding to the second site interfered with MMP9 binding to collagen IV, acting as a competitive inhibitor. Interestingly, modulation of collagen IV degradation by inactive forms of MMP2 also occurred in a cell-based system, revealing that this interrelationship affected neutrophil migration across a collagen IV membrane. The regulation of the proteolytic processing by a catalytically inactive domain (i.e., CBD) suggests that the two gelatinases might cooperate in degrading substrates even when either one is inactive. This observation reinforces the idea of exosite targets for MMP inhibitors, which should include all macromolecular substrate recognition sites.
Adrenal hormones mediate disease tolerance in malaria
Publisher: Springer Science and Business Media LLC
Date: 30-10-2018
DOI: 10.1038/S41467-018-06986-5
Abstract: Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance.
Recombinant Protein-Based Nanoparticles: Elucidating Their Inflammatory Effects In Vivo and Their Potential as a New Therapeutic Format
Publisher: MDPI AG
Date: 13-05-2020
DOI: 10.3390/PHARMACEUTICS12050450
Abstract: Bacterial inclusion bodies (IBs) are protein-based nanoparticles of a few hundred nanometers formed during recombinant protein production processes in different bacterial hosts. IBs contain active protein in a mechanically stable nanostructured format that has been broadly characterized, showing promising potential in different fields such as tissue engineering, protein replacement therapies, cancer, and biotechnology. For immunomodulatory purposes, however, the interference of the format immunogenic properties—intrinsic to IBs—with the specific effects of the therapeutic protein is still an uncovered gap. For that, active and inactive forms of the catalytic domain of a matrix metalloproteinase-9 (MMP-9 and mutMMP-9, respectively) have been produced as IBs and compared with the soluble form for dermal inflammatory effects in mmp9 knock-out mice. After protein injections in air-pouches in the mouse model, MMP-9 IBs induce local neutrophil recruitment and increase pro-inflammatory chemokine levels, lasting for at least two days, whereas the effects triggered by the soluble MMP-9 format fade out after 3 h. Interestingly, the IB intrinsic effects (mutMMP-9 IBs) do not last more than 24 h. Therefore, it may be concluded that IBs could be used for the delivery of therapeutic proteins, such as immunomodulating proteins while preserving their stability in the specific tissue and without triggering important unspecific inflammatory responses due to the protein format.
Inhibitory cytokines and cytokine inhibitors
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1995
DOI: 10.1212/WNL.45.6_SUPPL_6.S39
Abstract: Cytokines such as interleukin-1 and tumor necrosis factor are involved in the triggering of the immune response, induction of acute inflammatory events, and transition to, or persistence of, chronic inflammation. The action of proinflammatory cytokines is regulated by their receptor expression, downregulation and shedding, by specific inhibitors, and by inhibitory cytokines mainly produced by lymphocytes. This review aims to pinpoint recent findings in the assessment of the biologic activities of cytokine inhibitors and inhibitory cytokines. The suitability of these agents as therapeutic tools is discussed.
Distinct Expression patterns and Levels of Enzymatic Activity of Matrix Metalloproteinases and Their Inhibitors in primary Brain Tumors
Publisher: Oxford University Press (OUP)
Date: 06-2001
Abstract: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been implicated in the immense invasive potential and neovascularization of primary brain tumors. We investigated the gene expression profiles of MMPs 1, 2, 3, 7, 9, 12, 13, 14, 16 and of TIMPs 1, 2, 3, and 4 in various primary brain tumors (astrocytoma WHO grade I-III, glioblastoma, PNET, ependymoma III and oligoastrocytoma II) using novel RNase protection assay probe sets. In addition, we determined the level and cellular source of gelatinolytic activity and localized gelatinase B and TIMP-1 RNA. Distinct expression patterns of the MMP and TIMP genes were found in the various brain tumors tested. While the WHO grade I and II tumors had MT1/MT3 ratios below 1, the malignant (grade III and IV) tumors had ratios above 1. Strong expression of TIMP-1 RNA was observed in all malignant tumors and in grade I pilocytic astrocytomas and localized to the walls of neovessels. Quantitative analysis of enzymatic activity in the soluble fraction of protein extracts revealed that in most tumors gelatinases remained in the inactive pro-form. In situ zymography revealed net gelatinolytic activity in neurons of normal brain and in tumor cells and vessel walls of all tumors tested. Immunohistochemistry demonstrated that gelatinase B was localized to vessel walls, to neutrophils in areas of hemorrhage, and in glioblastomas to macrophages. Together these data demonstrate that the different primary brain tumors show distinct regulation of MMP and TIMP genes. The localization of the soluble gelatinase B indicates an association with neovascularization, whereas membrane-bound MMPs may account for the invasive potential of the glial tumor cells.
Focal MMP-2 and MMP-9 Activity at the Blood-Brain Barrier Promotes Chemokine-Induced Leukocyte Migration
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.CELREP.2015.01.037
Abstract: Although chemokines are sufficient for chemotaxis of various cells, increasing evidence exists for their fine-tuning by selective proteolytic processing. Using a model of immune cell chemotaxis into the CNS (experimental autoimmune encephalomyelitis [EAE]) that permits precise localization of immigrating leukocytes at the blood-brain barrier, we show that, whereas chemokines are required for leukocyte migration into the CNS, additional MMP-2/9 activities specifically at the border of the CNS parenchyma strongly enhance this transmigration process. Cytokines derived from infiltrating leukocytes regulate MMP-2/9 activity at the parenchymal border, which in turn promotes astrocyte secretion of chemokines and differentially modulates the activity of different chemokines at the CNS border, thereby promoting leukocyte migration out of the cuff. Hence, cytokines, chemokines, and cytokine-induced MMP-2/9 activity specifically at the inflammatory border collectively act to accelerate leukocyte chemotaxis across the parenchymal border.
Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis
Publisher: Rockefeller University Press
Date: 03-04-2006
DOI: 10.1084/JEM.20051342
Abstract: The endothelial cell monolayer of cerebral vessels and its basement membrane (BM) are ensheathed by the astrocyte endfeet, the leptomeningeal cells, and their associated parenchymal BM, all of which contribute to establishment of the blood–brain barrier (BBB). As a consequence of this unique structure, leukocyte penetration of cerebral vessels is a multistep event. In mouse experimental autoimmune encephalomyelitis (EAE), a widely used central nervous system inflammatory model, leukocytes first penetrate the endothelial cell monolayer and underlying BM using integrin β1-mediated processes, but mechanisms used to penetrate the second barrier defined by the parenchymal BM and glia limitans remain uninvestigated. We show here that macrophage-derived gelatinase (matrix metalloproteinase [MMP]-2 and MMP-9) activity is crucial for leukocyte penetration of the parenchymal BM. Dystroglycan, a transmembrane receptor that anchors astrocyte endfeet to the parenchymal BM via high affinity interactions with laminins 1 and 2, perlecan and agrin, is identified as a specific substrate of MMP-2 and MMP-9. Ablation of both MMP-2 and MMP-9 in double knockout mice confers resistance to EAE by inhibiting dystroglycan cleavage and preventing leukocyte infiltration. This is the first description of selective in situ proteolytic damage of a BBB-specific molecule at sites of leukocyte infiltration.
Imaging matrix metalloproteinase activity in multiple sclerosis as a specific marker of leukocyte penetration of the blood-brain barrier
Publisher: American Association for the Advancement of Science (AAAS)
Date: 09-11-2016
DOI: 10.1126/SCITRANSLMED.AAF8020
Abstract: A method to visualize MMPs reveals penetration of the blood-brain barrier by leukocytes early in multiple sclerosis.
Related Organisations
National Fund For Scientific Research (F.R.S.-FNRS)
Location: Belgium
Royal College Of Physicians
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
National Fund For Scientific Research Belgium (NFWO)
Location: Belgium
Related Funding Activities
No related grants have been discovered for Ghislain Opdenakker.