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

Hermans, Doryssa; Houben, Evelien; Baeten, Paulien; Slaets, Helena; Janssens, Kris; Hoeks, Cindy; Hosseinkhani, Baharak; Duran, Gayel; Bormans, Seppe; Gowing, Elizabeth; Hoornaert, Chloé; Beckers, Lien; Fung, Wing Ka; Schroten, Horst; Ishikawa, Hiroshi; Fraussen, Judith; Thoelen, Ronald; Vries, Helga E. de; Kooij, Gijs; Zandee, Stéphanie; Prat, Alexandre; Hellings, Niels; Broux, Bieke

doi:10.1007/s00401-022-02445-0

Cited by 19 publications

(13 citation statements)

References 71 publications

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“…For migration assays, the Boyden chamber migration assay was used as described before [31, 71]. hCMEC/D3 were trypsinized and cultured in collagen-coated Thincerts (24 well, translucent, 3 μm, Greiner Bio-One) at a density of 25×10 3 cells/cm².…”

Section: Methodsmentioning

confidence: 99%

“…To identify whether BBB-endothelial cells (ECs) are responsible for Treg instability, we used the human brain endothelial cell line hCMEC/D3 in a modified Boyden chamber migration assay to mimic the inflamed MS BBB in vitro (Fig. 1F) [31]. This model enables us to look at the direct effect of BBB-ECs on Treg function.…”

Section: Loss Of Phenotype and Function In Bbb-transmigrated Tregsmentioning

confidence: 99%

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Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

Baeten

Hamad

Hoeks

et al. 2022

Preprint

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In many autoimmune diseases, FOXP3+regulatory T cells (Tregs) skew towards a pro-inflammatory and non-suppressive phenotype and are therefore unable to control the exaggerated autoimmune response. This may largely impact the success of autologous Treg therapy which is currently under investigation for treatment of autoimmune diseases, including multiple sclerosis (MS). Thus, there is a need to ensurein vivostability of Tregs before successful Treg therapy can be applied. Using a murine genetic fate-mapping model, we demonstrate that inflammatory exFOXP3 T cells accumulate in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). In a humanin vitroBBB model, we discovered that interaction with inflamed blood-brain barrier (BBB)-endothelial cells induces loss of suppressive function in Tregs. Transcriptome analysis further revealed that Tregs which migrated across inflamed BBB-endothelial cellsin vitrohave a pro-inflammatory Th1/17 signature and upregulate the mTORC1 signaling pathway compared to non-migrated Tregs. These findings suggest that interaction with BBB-endothelial cells is sufficient to affect Treg function, and that transmigration triggers an additive pro-inflammatory phenotype switch, which was also seen in CNS-derived exFOXP3 T cells of EAE mice.In vitrotreatment of migrated human Tregs with the clinically-approved mTORC1 inhibitor rapamycin completely restored the loss of suppressive function. Finally, flow cytometric analysis indicated an enrichment of inflammatory, less suppressive CD49d+Tregs in the cerebrospinal fluid of MS patients, thereby underscoring the relevance of our findings for human disease. In sum, our findings provide firm evidence that the inflamed BBB affects human Treg stability, which can be restored using a mTORC1 inhibitor. These insights can help in significantly improving the efficacy of autologous Treg therapy of MS.

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Section: Methodsmentioning

confidence: 99%

Section: Loss Of Phenotype and Function In Bbb-transmigrated Tregsmentioning

confidence: 99%

Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

Baeten

Hamad

Hoeks

et al. 2022

Preprint

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“…In an animal MS model (experimental autoimmune encephalitis), Hermans et al [ 180 ] have identified a role of the oncostatin-M/CCL20 axis in BBB impairment and T helper 17 cell recruitment. While BBB dysfunction may be secondary to neuroinflammation, Nishihara et al [ 181 ] found evidence of an intrinsic BBB impairment with MS when comparing iPSC-derived BMEC-like cells from control and MS patients.…”

Section: Neurological Disordersmentioning

confidence: 99%

A year in review: brain barriers and brain fluids research in 2022

Keep

Jones

Hamilton

et al. 2023

Fluids Barriers CNS

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This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

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“… 35 All of these cell types cause an inflammatory cascade in the CNS by releasing chemokines and pro-inflammatory cytokines such as IFN-γ, IL-2, tumor necrosis factor alpha (TNF-α) and oncostatin M (OSM). 2 , 36 , 37 As a consequence, the BBB becomes inflamed and other immune cells like B cells and macrophages are recruited and activated. In MS, activated B cells were shown to excessively produce the cytokines lymphotoxin, TNF-α and granulocyte macrophage-colony stimulating factor (GM-CSF), next to their extensive antibody production marking the myelin for phagocytosis.…”

Section: Ms Immunopathologymentioning

confidence: 99%

Regulatory T cell therapy for multiple sclerosis: Breaching (blood-brain) barriers

Verreycken

Baeten

Broux

2022

Human Vaccines & Immunotherapeutics

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Multiple sclerosis (MS) is an autoimmune disorder causing demyelination and neurodegeneration in the central nervous system. MS is characterized by disturbed motor performance and cognitive impairment. Current MS treatments delay disease progression and reduce relapse rates with general immunomodulation, yet curative therapies are still lacking. Regulatory T cells (Tregs) are able to suppress autoreactive immune cells, which drive MS pathology. However, Tregs are functionally impaired in people with MS. Interestingly, Tregs were recently reported to also have regenerative capacity. Therefore, experts agree that Treg cell therapy has the potential to ameliorate the disease. However, to perform their local anti-inflammatory and regenerative functions in the brain, they must first migrate across the blood-brain barrier (BBB). This review summarizes the reported results concerning the migration of Tregs across the BBB and the influence of Tregs on migration of other immune subsets. Finally, their therapeutic potential is discussed in the context of MS.

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

Cited by 19 publications

References 71 publications

Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

Rapamycin rescues loss-of-function in blood-brain barrier-interacting regulatory T cells

A year in review: brain barriers and brain fluids research in 2022

Regulatory T cell therapy for multiple sclerosis: Breaching (blood-brain) barriers

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