Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/37568
Title: Oncostatin M triggers brain inflammation by compromising blood-brain barrier integrity
Authors: HERMANS, Doryssa 
HOUBEN, Evelien 
BAETEN, Paulien 
Slaets, Helena
JANSSENS, Kris 
HOEKS, Cindy 
HOSSEINKHANI, Baharak 
DURAN, Gayel 
BORMANS, Seppe 
Gowing, Elizabeth
Hoornaert , Chloe
BECKERS, Lien 
Fung, Wing Ka
Schroten, Horst
Ishikawa, Hiroshi
FRAUSSEN, Judith 
THOELEN, Ronald 
de Vries, Helga E.
Kooij, Gijs
Zandee, Stephanie
Prat, Alexandre
HELLINGS, Niels 
BROUX, Bieke 
Issue Date: 2022
Publisher: SPRINGER
Source: ACTA NEUROPATHOLOGICA,
Status: Early view
Abstract: Oncostatin M (OSM) is an IL-6 family member which exerts neuroprotective and remyelination-promoting effects after damage to the central nervous system (CNS). However, the role of OSM in neuro-inflammation is poorly understood. Here, we investigated OSM's role in pathological events important for the neuro-inflammatory disorder multiple sclerosis (MS). We show that OSM receptor (OSMR beta) expression is increased on circulating lymphocytes of MS patients, indicating their elevated responsiveness to OSM signalling. In addition, OSM production by activated myeloid cells and astrocytes is increased in MS brain lesions. In experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS, OSMR beta-deficient mice exhibit milder clinical symptoms, accompanied by diminished T helper 17 (Th17) cell infiltration into the CNS and reduced BBB leakage. In vitro, OSM reduces BBB integrity by downregulating the junctional molecules claudin-5 and VE-cadherin, while promoting secretion of the Th17-attracting chemokine CCL20 by inflamed BBB-endothelial cells and reactive astrocytes. Using flow cytometric fluorescence resonance energy transfer (FRET) quantification, we found that OSM-induced endothelial CCL20 promotes activation of lymphocyte function-associated antigen 1 (LFA-1) on Th17 cells. Moreover, CCL20 enhances Th17 cell adhesion to OSM-treated inflamed endothelial cells, which is at least in part ICAM-1 mediated. Together, these data identify an OSM-CCL20 axis, in which OSM contributes significantly to BBB impairment during neuro-inflammation by inducing permeability while recruiting Th17 cells via enhanced endothelial CCL20 secretion and integrin activation. Therefore, care should be taken when considering OSM as a therapeutic agent for treatment of neuro-inflammatory diseases such as MS.
Notes: Broux, B (corresponding author), Univ MS Ctr, Campus Diepenbeek, Diepenbeek, Belgium.; Broux, B (corresponding author), UHasselt, Dept Immunol & Infect, Neuro Immune Connect & Repair Lab, Biomed Res Inst, Diepenbeek, Belgium.; Broux, B (corresponding author), Maastricht Univ, Cardiovasc Res Inst Maastricht, Dept Internal Med, Maastricht, Netherlands.
Bieke.broux@uhasselt.be
Keywords: Oncostatin M;T helper 17 cells;Endothelial cells;Blood-brain barrier;Neuroinflammation;Multiple sclerosis
Document URI: http://hdl.handle.net/1942/37568
ISSN: 0001-6322
e-ISSN: 1432-0533
DOI: 10.1007/s00401-022-02445-0
ISI #: WOS:000806674800001
Rights: The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022
Category: A1
Type: Journal Contribution
Appears in Collections:Research publications

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