Interaction between Neurons and the Oligodendroglial Lineage in Multiple Sclerosis and Its Preclinical Models.
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ABSTRACT:
SUBMITTER: Pantazou V
PROVIDER: S-EPMC7999210 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Monoclonal antibodies (mAb) are promising therapeutics in multiple sclerosis and multiple new candidates have been developed, hence increasing the need for some agreement for preclinical mAb studies. We systematically analyzed publications of experimental autoimmune encephalomyelitis (EAE) studies showing effects of monoclonal antibodies. A PubMed search retrieved 570 records, out of which 122 studies with 253 experiments were eligible based on experimental design, number of animals and presentation of time courses of EAE scores. Analysis of EAE models, treatment schedules, single and total doses, routes of administration, and onset of treatment from pre-immunization up to 35 days after immunization revealed high heterogeneity. Total doses ranged from 0.1 to 360 mg/kg for observation times of up to 35 days after immunization. About half of experiments (142/253) used total doses of 10-70 mg/kg. Employing this range, we tested anti-Itga4 as a reference mAb at varying schedules and got no, mild or substantial EAE-score reductions, depending on the mouse strain and onset of the treatment. The result agrees with the range of outcomes achieved in 10 reported anti-Itga4 experiments. Studies comparing low and high doses of various mAbs or early vs. late onset of treatment did not reveal dose-effect or timing-effect associations, with a tendency towards better outcomes with preventive treatments starting within the first week after immunization. The systematic comparison allows for extraction of some "common" design characteristics, which may be helpful to further assess the efficacy of mAbs and role of specific targets in preclinical models of multiple sclerosis.
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Project description:Multiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and defective remyelination in MS are currently unknown. To determine whether intrinsic oligodendroglial factors contribute to impaired remyelination in relapsing-remitting MS (RRMS), we compared induced pluripotent stem cell-derived oligodendrocytes (hiOL) from RRMS patients and controls, among them two monozygous twin pairs discordant for MS. We found that hiOL from RRMS patients and controls were virtually indistinguishable with respect to remyelination-associated functions and proteomic composition. However, while analyzing the effect of extrinsic factors we discovered that supernatants of activated peripheral blood mononuclear cells (PBMCs) significantly inhibit oligodendroglial differentiation. In particular, we identified CD4+ T cells as mediators of impaired oligodendroglial differentiation; at least partly due to interferon-gamma secretion. Additionally, we observed that blocked oligodendroglial differentiation induced by PBMC supernatants could not be restored by application of oligodendroglial differentiation promoting drugs, whereas treatment of PBMCs with the immunomodulatory drug teriflunomide prior to supernatant collection partly rescued oligodendroglial differentiation. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors but rather caused by the inflammatory environment in RRMS lesions which underlines the need for drug screening approaches taking the inflammatory environment into account. Combined, these findings may contribute to the development of new remyelination promoting strategies.
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Project description:The PI3K/AKT/mTOR pathway is an intracellular signalling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Multiple Sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS and on oligodendrocyte function, making use of currently available whole-genome transcriptomic data. Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aim, the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells. Our data indicate that there is a significant involvement of the mTOR network in the etiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in this clinical setting. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury. Overall, our study suggests that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability.
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Project description:Differentiation of oligodendroglial progenitor cells (OPCs) into myelinating oligodendrocytes is known to be regulated by the microenvironment where they differentiate. However, current research has not verified whether or not oligodendroglial lineage cells (OLCs) derived from different anatomical regions of the central nervous system (CNS) respond to microenvironmental cues in the same manner. Here, we isolated pure OPCs from rat neonatal forebrain (FB) and spinal cord (SC) and compared their phenotypes in the same in vitro conditions. We found that although FB and SC OLCs responded differently to the same external factors; they were distinct in proliferation response to mitogens, oligodendrocyte phenotype after differentiation, and cytotoxic responses to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-type glutamate receptor-mediated excitotoxicity at immature stages of differentiation in a cell-intrinsic manner. Moreover, transcriptome analysis identified genes differentially expressed between these OPC populations, including those encoding transcription factors (TFs), cell surface molecules, and signaling molecules. Particularly, FB and SC OPCs retained the expression of FB- or SC-specific TFs, such as Foxg1 and Hoxc8, respectively, even after serial passaging in vitro. Given the essential role of these TFs in the regional identities of CNS cells along the rostrocaudal axis, our results suggest that CNS region-specific gene regulation by these TFs may cause cell-intrinsic differences in cellular responses between FB and SC OLCs to extracellular molecules. Further understanding of the regional differences among OPC populations will help to improve treatments for demyelination in different CNS regions and to facilitate the development of stem cell-derived OPCs for cell transplantation therapies for demyelination. Cover Image for this issue: doi. 10.1111/jnc.13809.
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Project description:Multiple sclerosis (MS) is the most frequent demyelinating disease and despite significant advances in the immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair process, represents a promising new treatment approach. However, spontaneous remyelination frequently fails in MS lesions due to an impaired differentiation of progenitor cells into mature, myelinating oligodendrocytes. Intrinsic oligodendroglial and extrinsic inflammatory factors may contribute to this differentiation block. Therefore, we compared induced pluripotent stem cell (iPSC)-derived oligodendrocytes (hiOL) from MS patients and healthy controls as well as their response to extrinsic factors. While functional capabilities or proteome compostion of both cell types were virtually indistinguishable, we discovered that Interferon-gamma (IFNγ) producing immune cells significantly impaired oligodendroglial differentiation and observed no differences in the functional capabilities or the proteome. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors, but rather caused by the inflammatory environment present in MS lesions. These findings may contribute to the development of remyelination promoting strategies in MS.
2020-09-04 | PXD016043 | Pride
Project description:Multiple sclerosis is a neurodegenerative disease associated with demyelination and neuroinflammation in the central nervous system. There is an urgent need to develop remyelinating therapies to better treat multiple sclerosis and other demyelinating diseases. The kappa opioid receptor (KOR) has been identified as a potential target for the development of remyelinating therapies; however, prototypical KOR agonists, such as U50,488 have side effects, which limit clinical use. In the current study, we investigated a Salvinorin A analog, ethoxymethyl ether Salvinorin B (EOM SalB) in two preclinical models of demyelination in C57BL/6J mice. We showed that in cellular assays EOM SalB was G-protein biased, an effect often correlated with fewer KOR-mediated side effects. In the experimental autoimmune encephalomyelitis model, we found that EOM SalB (0.1-0.3 mg/kg) effectively decreased disease severity in a KOR-dependent manner and led to a greater number of animals in recovery compared to U50,488 treatment. Furthermore, EOM SalB treatment decreased immune cell infiltration and increased myelin levels in the central nervous system. In the cuprizone-induced demyelination model, we showed that EOM SalB (0.3 mg/kg) administration led to an increase in the number of mature oligodendrocytes, the number of myelinated axons and the myelin thickness in the corpus callosum. Overall, EOM SalB was effective in two preclinical models of multiple sclerosis and demyelination, adding further evidence to show KOR agonists are a promising target for remyelinating therapies.
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Project description:The excitotoxin quinolinic acid, a by-product of the kynurenine pathway, is known to be involved in several neurological diseases including multiple sclerosis (MS). Quinolinic acid levels are elevated in experimental autoimmune encephalomyelitis rodents, the widely used animal model of MS. Our group has also found pathophysiological concentrations of quinolinic acid in MS patients. This led us to investigate the effect of quinolinic acid on oligodendrocytes; the main cell type targeted by the autoimmune response in MS. We have examined the kynurenine pathway (KP) profile of two oligodendrocyte cell lines and show that these cells have a limited threshold to catabolize exogenous quinolinic acid. We further propose and demonstrate two strategies to limit quinolinic acid gliotoxicity: 1) by neutralizing quinolinic acid's effects with anti-quinolinic acid monoclonal antibodies and 2) directly inhibiting quinolinic acid production from activated monocytic cells using specific KP enzyme inhibitors. The outcome of this study provides a new insight into therapeutic strategies for limiting quinolinic acid-induced neurodegeneration, especially in neurological disorders that target oligodendrocytes, such as MS.
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Project description:We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13:03-*03:01 OR = 3.3, Pc 5.1 × 10(-5), *04:05-*03:01 OR = 2.1, Pc 9.7 × 10(-8), *15:01-*06:02 OR = 2.0, Pc = 9.1 × 10(-3), *03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) and protection (*11, OR = 0.8, Pc = 2.7 × 10(-2), *16:01-*05:02 OR = 0.6, Pc = 4.8 × 10(-16), *14:01-4-*05:031 = OR = 0.5, Pc = 9.8 × 10(-4) and *15:02-*06:01 OR = 0.4, Pc = 5.1 × 10(-4)). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14:01, *04:05, *13?03, *08:01 and *03:01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85-99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.
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Project description:Multiple system atrophy is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of α-synuclein in oligodendrocytes. To understand how α-synuclein aggregates impact oligodendroglial homeostasis, we investigated an oligodendroglial cell model of α-synuclein dependent degeneration and identified responses linked to the NF-κB transcription factor stress system. Coexpression of human α-synuclein and the oligodendroglial protein p25α increased the expression of IκBα mRNA and protein early during the degenerative process and this was dependent on both aggregation and Ser129 phosphorylation of α-synuclein. This response was prodegenerative because blocking IκBα expression by siRNA rescued the cells. IκBα is an inhibitor of NF-κB and acts by binding and retaining NF-κB p65 in the cytoplasm. The protection obtained by silencing IκBα was accompanied by a strong increase in nuclear p65 translocation indicating that NF-κB activation protects against α-synuclein aggregate stress. In the cellular model, two different phenotypes were observed; degenerating cells retracting their microtubules and resilient cells tolerating the coexpression of α-synuclein and p25α. The resilient cells displayed a significant higher nuclear translocation of p65 and activation of the NF-κB system relied on stress elicited by aggregated and Ser129 phosphorylated α-synuclein. To validate the relationship between oligodendroglial α-synuclein expression and IκBα, we analyzed two different lines of transgenic mice expressing human α-synuclein under the control of the oligodendrocytic MBP promotor (intermediate-expresser line 1 and high-expresser line 29). IκBα mRNA expression was increased in both lines and immunofluorescence microscopy and in situ hybridization revealed that IκBα mRNA and protein is expressed in oligodendrocytes. IκBα mRNA expression was demonstrated prior to activation of microglia and astrocytes in line 1. Human brain tissue affected by MSA displayed increased expression of IκBα and NF-κB p65 in some oligodendrocytes containing glial cytoplasmic inclusions. Our data suggest that oligodendroglial IκBα expression and NF-κB are activated early in the course of MSA and their balance contributes to the decision of cellular demise. Favoring oligodendroglial NF-κB activation may represent a therapeutic strategy for this devastating disease.
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