TY - JOUR
T1 - Oncostatin M triggers brain inflammation by compromising blood–brain barrier integrity
AU - Hermans, Doryssa
AU - Houben, Evelien
AU - Baeten, Paulien
AU - Slaets, Helena
AU - Janssens, Kris
AU - Hoeks, Cindy
AU - Hosseinkhani, Baharak
AU - Duran, Gayel
AU - Bormans, Seppe
AU - Gowing, Elizabeth
AU - Hoornaert, Chloé
AU - Beckers, Lien
AU - Fung, Wing Ka
AU - Schroten, Horst
AU - Ishikawa, Hiroshi
AU - Fraussen, Judith
AU - Thoelen, Ronald
AU - de Vries, Helga E.
AU - Kooij, Gijs
AU - Zandee, Stephanie
AU - Prat, Alexandre
AU - Hellings, Niels
AU - Broux, Bieke
N1 - Funding Information: This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen, G097318N), Bijzonder Onderzoeksfonds (BOF) UHasselt and the Fondation Charcot. The hCMEC/D3 cell line was provided by Tebu-bio (Le Perray-en-Yvelines, France). OSMRβ KO mice (B6.129S-Osmr ) were provided by the RIKEN BRC through the National Bio-Resource Project of MEXT, Japan. We would like to thank Lyne Bourbonnière for assistance in HBMEC culture, Dr. Antoine Fournier, Marc Charabati and Sam Duwé for technical assistance, and Britt Coenen, Athanasios Bethanis, Jules Teuwen, Ina Vantyghem and Kardelen Irem Isin for their practical help with experiments. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/8
Y1 - 2022/8
N2 - 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 (OSMRβ) 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, OSMRβ-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.
AB - 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 (OSMRβ) 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, OSMRβ-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.
KW - Blood–brain barrier
KW - Endothelial cells
KW - Multiple sclerosis
KW - Neuroinflammation
KW - Oncostatin M
KW - T helper 17 cells
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85131438645&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/35666306
U2 - https://doi.org/10.1007/s00401-022-02445-0
DO - https://doi.org/10.1007/s00401-022-02445-0
M3 - Article
C2 - 35666306
SN - 0001-6322
VL - 144
SP - 259
EP - 281
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -