Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

Houben, Evelien; Janssens, Kris; Hermans, Doryssa; Vandooren, Jennifer; Haute, Chris Van den; Schepers, Melissa; Vanmierlo, Tim; Lambrichts, Ivo; Horssen, Jack van; Baekelandt, Veerle; Opdenakker, Ghislain; Baron, Wia; Broux, Bieke; Slaets, Helena; Hellings, Niels

doi:10.1073/pnas.1912910117

Cited by 33 publications

(34 citation statements)

References 62 publications

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“…Additionally, also astrocytes may influence the outcome of remyelination. They can be beneficial for remyelination by promotion of oligodendroglial differentiation and providing of cholesterol for new myelin sheaths, but have been also shown to impair remyelination by either activating remyelination inhibiting pathways such as the JAG1-NOTCH1 pathway or by modulating the extracellular matrix [10,32,35,61,72]. One also has to keep in mind that the biopsies were taken from patients with an untypical clinical presentation and, therefore, might not be representative for MS patients with a more typical disease onset.…”

Section: Discussionmentioning

confidence: 99%

Lesion stage-dependent causes for impaired remyelination in MS

et al. 2020

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Multiple sclerosis (MS) is the most frequent demyelinating disease and a leading cause for disability in young adults. Despite significant advances in immunotherapies in recent years, disease progression still cannot be prevented. Remyelination, meaning the formation of new myelin sheaths after a demyelinating event, can fail in MS lesions. Impaired differentiation of progenitor cells into myelinating oligodendrocytes may contribute to remyelination failure and, therefore, the development of pharmacological approaches which promote oligodendroglial differentiation and by that remyelination, represents a promising new treatment approach. However, this generally accepted concept has been challenged recently. To further understand mechanisms contributing to remyelination failure in MS, we combined detailed histological analyses assessing oligodendroglial cell numbers, presence of remyelination as well as the inflammatory environment in different MS lesion types in white matter with in vitro experiments using induced-pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) and supernatants from polarized human microglia. Our findings suggest that there are multiple reasons for remyelination failure in MS which are dependent on lesion stage. These include lack of myelin sheath formation despite the presence of mature oligodendrocytes in a subset of active lesions as well as oligodendroglial loss and a hostile tissue environment in mixed active/inactive lesions. Therefore, we conclude that better in vivo and in vitro models which mimic the pathological hallmarks of the different MS lesion types are required for the successful development of remyelination promoting drugs.

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Section: Discussionmentioning

confidence: 99%

Lesion stage-dependent causes for impaired remyelination in MS

et al. 2020

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“…In the context of a traumatic lesion of the CNS, MMPs including Timp1 are critical for synaptic recovery following axonal injury, mediating secondary degeneration and regulating angiogenesis and glial scar formation [ 47 ]. Timp1 also has pro-oligodendroglial properties in different in vitro contexts which promote OPC maturation [ 48 ] and in vivo inhibition of Timp1 activity completely abolishes spontaneous remyelination [ 49 ]. This protein is also associated with various integrins, including ItgaV, Itgb1 and Itgb3, which are involved in OPC differentiation into myelinating oligodendrocytes [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Time-Course Changes of Extracellular Matrix Encoding Genes Expression Level in the Spinal Cord Following Contusion Injury—A Data-Driven Approach

Bighinati

Khalajzeyqami

Baldassarro

et al. 2021

IJMS

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The involvement of the extracellular matrix (ECM) in lesion evolution and functional outcome is well recognized in spinal cord injury. Most attention has been dedicated to the “core” area of the lesion and scar formation, while only scattered reports consider ECM modification based on the temporal evolution and the segments adjacent to the lesion. In this study, we investigated the expression profile of 100 genes encoding for ECM proteins at 1, 8 and 45 days post-injury, in the spinal cord segments rostral and caudal to the lesion and in the scar segment, in a rat model. During both the active lesion phases and the lesion stabilization, we observed an asymmetric gene expression induced by the injury, with a higher regulation in the rostral segment of genes involved in ECM remodeling, adhesion and cell migration. Using bioinformatic approaches, the metalloproteases inhibitor Timp1 and the hyaluronan receptor Cd44 emerged as the hub genes at all post-lesion times. Results from the bioinformatic gene expression analysis were then confirmed at protein level by tissue analysis and by cell culture using primary astrocytes. These results indicated that ECM regulation also takes place outside of the lesion area in spinal cord injury.

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“…We found that Dectin-1 promotes expression of Osm, a cytokine with described protective functions in cuprizone-induced demyelination 17,77 and other models of neuropathology 16,37 . Osm protein is expressed in MS brains 38 and is elevated in supernatants of cultured PBMCs from MS patients 39 .…”

Section: Studies On Clrs In Eae and Related Models Have Mostly Focusementioning

confidence: 79%

Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

Deerhake

Danzaki

Inoue

et al. 2020

Preprint

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Pathologic roles for innate immunity in neurologic disorders are well-described, but protective aspects of the immune response are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. However, we found that Dectin-1 is protective in experimental autoimmune encephalomyelitis (EAE), while its canonical signaling mediator, Card9, promotes the disease. Notably, Dectin-1 does not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Myeloid cells mediate the protective function of Dectin-1 in EAE and upregulate gene expression of neuroprotective molecules, including Oncostatin M (Osm) through a non-canonical Card9-independent pathway, mediated by NFAT. Furthermore, we found that the Osm receptor (OsmR) functions specifically in astrocytes to reduce EAE severity. Our study revealed a new mechanism of protective myeloid-astrocyte crosstalk regulated by a non-canonical Dectin-1 pathway and identifies novel therapeutic targets for CNS autoimmunity.development. We found that non-canonical Card9-independent Dectin-1 signaling involving NFAT drives expression of Oncostatin M (Osm), an IL-6 family cytokine with neuroprotective functions 16,17,18 , and signaling through the Osm receptor (OsmR) on astrocytes reduces disease progression and promotes recovery in EAE. Furthermore, we identified a Card9-independent Dectin-1-mediated transcriptional program driving expression of Osm and other neuroprotective genes. Our findings provoke a re-consideration of Dectin-1 signaling and functions by identifying a new mechanism of protective myeloid-astrocyte communication in CNS autoimmunity. RESULTS Elevated gene expression of the C-type lectin receptor, Dectin-1 (CLEC7A) in MS lesionsWe evaluated gene expression of CLRs in multiple datasets profiling MS brain lesions 18 .Among genes encoding CLRs with known immune functions, CLEC7A (Dectin-1) and CLEC4A (DCIR), closely linked on chromosome 12, were notable for their elevated expression in MS brain specimens in two independent datasets ( Supplementary Fig. 1a-c) 19, 20, 21 , suggesting possible involvement of Dectin-1 and DCIR in MS. In EAE, DCIR has been reported to be protective 22,23 but the function of Dectin-1 in CNS autoimmunity remained unknown. Dectin-1 is a protective C-type lectin receptor in EAENext, we sought to test the function of Dectin-1 in CNS autoimmunity using EAE induced with the MOG35−55 autoantigen peptide. We initially hypothesized that Dectin-1 may exacerbate EAE severity by promoting IL-1β expression and Th17 differentiation, given its known role in antifungal immunity 3, 4 and the pathogenicity of Th17 cells in EAE development 24 . Instead, we found that Dectin-1-deficient (Clec7a -/-) mice developed more severe disease than WT mice (Fig. 1a). A mild EAE induction with a reduced amount of adjuvant also showed the protective effect of Dectin-1 (Fig. 1b). Next, we tested whether administering a Dectin-1 agonist was sufficient to limit EAE severity. To test this, we used hot alkali-depleted zymosan (d-zymosa...

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Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

Cited by 33 publications

References 62 publications

Lesion stage-dependent causes for impaired remyelination in MS

Lesion stage-dependent causes for impaired remyelination in MS

Time-Course Changes of Extracellular Matrix Encoding Genes Expression Level in the Spinal Cord Following Contusion Injury—A Data-Driven Approach

Dectin-1 limits central nervous system autoimmunity through a non-canonical pathway

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