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Oncostatin M triggers brain inflammation by compromising blood–brain barrier integrity

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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 (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.

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Acknowledgements

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 <tm1Mtan >) 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.

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Author notes

  1. Doryssa Hermans and Evelien Houben are equally contributing first authors. Bieke Broux and Niels Hellings are equally contributing senior authors.

Authors and Affiliations

  1. University MS Center, Campus Diepenbeek, Diepenbeek, Belgium

    Doryssa Hermans, Evelien Houben, Paulien Baeten, Helena Slaets, Kris Janssens, Cindy Hoeks, Baharak Hosseinkhani, Gayel Duran, Lien Beckers, Judith Fraussen, Niels Hellings & Bieke Broux

  2. Neuro-Immune Connections and Repair Lab, Department of Immunology and Infection, Biomedical Research Institute, UHasselt, Diepenbeek, Belgium

    Doryssa Hermans, Evelien Houben, Paulien Baeten, Helena Slaets, Kris Janssens, Cindy Hoeks, Baharak Hosseinkhani, Gayel Duran, Niels Hellings & Bieke Broux

  3. Institute for Materials Research (IMO), UHasselt, Diepenbeek, Belgium

    Seppe Bormans & Ronald Thoelen

  4. Centre de Recherche du CHUM (CRCHUM), Neuroimmunology Unit, Montreal, QC, Canada

    Elizabeth Gowing, Chloé Hoornaert, Stephanie Zandee & Alexandre Prat

  5. Department of Immunology and Infection, Biomedical Research Institute, UHasselt, Diepenbeek, Belgium

    Lien Beckers & Judith Fraussen

  6. Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands

    Wing Ka Fung, Helga E. de Vries & Gijs Kooij

  7. Pediatric Infectious Diseases, Medical Faculty Mannheim, University Children’s Hospital Mannheim, Heidelberg University, Mannheim, Germany

    Horst Schroten

  8. Laboratory of Clinical Regenerative Medicine, Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

    Hiroshi Ishikawa

  9. Department of Internal Medicine, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Bieke Broux

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  1. Doryssa Hermans
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Contributions

Conceptualization: BB, NH; methodology: DH, EH, PB, HS, KJ, CH, BH, GD, SB, EG, ChH, LB, KFW, JF, SZ, RT, AP; formal analysis: DH, EH, CH, KJ, JF, SZ; writing-original draft: DH, EH, KJ; writing-review and editing: BB, NH, HS, GK, HEdV; visualization: DH; supervision: BB, NH. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Bieke Broux.

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Supplementary Information

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401_2022_2445_MOESM1_ESM.tif

Supplementary file1 Suppl. Fig. 1 OSM does not affect the functional properties of activated CD4+ T cells, CD8+ T cells and CD19+ B cells. CD4+ T cells, CD8+ T cells and B cells were isolated from PBMCs of healthy donors using magnetic selection (n=5). (a, d, g) T and B cell proliferation were analysed with flow cytometry after 6 days of stimulation with αCD3/28/2-coated beads or CpG2006, respectively, in the absence or presence of OSM (25 ng/ml) and anti-LIFR antibody (20 µg/ml). (b, c) Flow cytometric analysis of IFNγ and IL17 expression by CD4+ T memory cells cultured under non-skewing and Th1 or Th17 skewing conditions in the presence or absence of OSM. (e, f) Concentration of IL4, IL17, IFNγ, granzyme A, granzyme B and perforin in the conditioned medium of resting or stimulated CD8+ T cells, in the absence or presence of OSM and anti-LIFR antibody, measured using LegendPlex™ multiplex assay. (h, i) Flow cytometric analysis of the percentage CD80+ activated B cells and CD24-CD38+ plasmablasts, respectively, in the absence or presence of OSM and anti-LIFR antibody. Data are depicted as mean ± SEM. Statistical analysis was performed using Wilcoxon test, one-way ANOVA and two-way ANOVA using Tukey’s multiple comparisons test with *p≤0.05, **p≤0.01, ***p≤0.001. OSM, oncostatin M; LIFR, leukemia inhibitory factor; IFNγ, interferon gamma; IL, interleukin (TIF 642 KB)

401_2022_2445_MOESM2_ESM.tif

Supplementary file2 Suppl. Fig. 2 Less severe EAE in OSMRβ-deficient mice is not attributable to an altered peripheral immune cell response. WT and OSMRβ KO mice were injected with MOG35-55 in CFA and 40 ng/100 µl PTX (WT: n=30; OSMRβ KO: n=33; pooled data of 3 independent experiments). Mice were sacrificed at onset (13 dpi; WT: n=5; KO: n=5), peak (19 dpi; WT: n=9; KO: n=6) and chronic phase of EAE (50 dpi; WT: n=5; KO: n=5). (a) Sum of EAE scores were evaluated. (b) Lymphocyte proliferation in response to MOG or ConA as measured by CFSE incorporation in splenocytes from WT and OSMRβ KO mice, 10 days after EAE induction (n=3/genotype). (c) Flow cytometric analysis of the percentage of CD4+ T cells within the live cell population. White and grey bars depict WT and OSMRβ KO mice, respectively. (d) Gating strategy of the immune cell profile in the CNS at EAE peak. Single cells are gated, using the area and height of the forward scatter (FSC-A, FSC-H). Dead cells are excluded using Zombie NIR. Lymphocytes are gated based on forward and sideward scatter (FSC-A, SSC-A). Next, leukocytes are characterized based on CD45. T and B cells are distinguished based on CD3 and CD19, respectively. Within the CD3+ T cell gate, CD4+ T helper cells and CD8+ cytotoxic T cells are identified. Finally, IFNγ, IL17 and Foxp3 are used to gate Th1 (Q4), Th17 (Q1) and T regulatory cells, respectively. (e,f) Absolute numbers of infiltrating Th1 and Th17 cells, respectively, were calculated by multiplying the percentage cells within the lymphocyte gate by the total amount of CNS-infiltrating cells, counted by an automated cell counter. (g) Positive correlation between % Th17 cells and absolute number of Th17 cells in pooled WT and OSMR KO mice (EAE score > 0), using simple linear regression. (h-m) Flow cytometric analysis of the percentage of CD8+ T cells and CD19+ B cells in lymph nodes, spleen and CNS, respectively. Statistical analysis was performed using two-way ANOVA and Sidak’s multiple comparisons test. Data are depicted as mean ± SEM. EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; ConA, Concanavalin A; WT, wild type; OSMRβ KO, oncostatin M receptor knock-out; IFNγ, interferon gamma; IL17, interleukin 17; Th, T helper cell (TIF 1511 KB)

401_2022_2445_MOESM3_ESM.tif

Supplementary file3 Suppl. Fig. 3 OSM-induced effects on mouse BBB-ECs are abrogated in absence of OSMRβ signalling. Primary MBMECs isolated from OSMRβ KO mice (n=5) were treated with 25 ng/ml OSM in the presence/absence of 10 ng/ml TNF-α/IFN-γ for 48h. (a) TEER was measured manually. Flow cytometric analysis of (b) ICAM-1 and (c) VCAM-1 expression depicted as median fluorescence intensity (MFI). Statistical analysis was performed using one-way ANOVA with matched data and Šidák’s multiple comparisons test with *p≤0.05, **p≤0.01, ***p≤0.001, ***p≤0.0001. Data are depicted as mean ± SEM. MFI: median fluorescence intensity; OSM, oncostatin M; ICAM-1, intercellular cell adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; TNFα, tumor necrosis factor alpha; IFNγ, interferon gamma; TEER, transendothelial electrical resistance (TIF 446 KB)

401_2022_2445_MOESM4_ESM.tif

Supplementary file4 Suppl. Fig. 4 ICAM-2 and ICAM-3 expression is not affected by OSM treatment. qPCR analysis of (a) ICAM-1, (b) ICAM-2 and (c) ICAM-3 OSMRβ mRNA hCMEC/D3 cells (n = 5) treated with 25 ng/ml OSM in the presence/absence of 10 ng/ml TNF-α/IFN-γ for 24h. Statistical analysis was performed using one-way ANOVA and Šidák’s multiple comparisons test with *p≤0.05, **p≤0.01, ***p≤0.001, ***p≤0.0001. Data are depicted as mean ± SEM. OSM, oncostatin M; TNFα, tumor necrosis factor alpha; IFNγ, interferon gamma; ICAM, intercellular cell adhesion molecule (TIF 457 KB)

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Hermans, D., Houben, E., Baeten, P. et al. Oncostatin M triggers brain inflammation by compromising blood–brain barrier integrity. Acta Neuropathol 144, 259–281 (2022). https://doi.org/10.1007/s00401-022-02445-0

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