scholarly journals Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengmeng Dou ◽  
Xueliang Zhou ◽  
Lifeng Li ◽  
Mingliang Zhang ◽  
Wenbin Wang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Target Genes ◽  
Immune Cell ◽  
Gene Expression Omnibus ◽  
Network Pharmacology ◽  
Autoimmune Encephalomyelitis ◽  
Data Set ◽  
Tissue Samples ◽  
Gene Data ◽  
Experimental Autoimmune

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

scholarly journals A Mushroom Extract Piwep fromPhellinus igniariusAmeliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lan Li ◽  
Guang Wu ◽  
Bo Young Choi ◽  
Bong Geom Jang ◽  
Jin Hee Kim ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Lymph Node ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Immune Cell Infiltration ◽  
Autoimmune Encephalomyelitis ◽  
Phellinus Igniarius ◽  
Mushroom Extract ◽  
Experimental Autoimmune

The present study aimed to evaluate the therapeutic potential of a mushroom extract fromPhellinus igniariusin an animal model of multiple sclerosis. The medicinal mushroom,Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract ofPhellinus igniarius(Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α4in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γin the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression.

scholarly journals Loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model

2018 ◽  
Vol 1 (5) ◽  
pp. e201800039 ◽  
Author(s):  
Lei Sun ◽  
Elphine Telles ◽  
Molly Karl ◽  
Fengdong Cheng ◽  
Noreen Luetteke ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Demyelinating Disease ◽  
Demyelinating Diseases ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). There is no known cure for MS, and currently available drugs for managing this disease are only effective early on and have many adverse side effects. Results from recent studies suggest that histone deacetylase (HDAC) inhibitors may be useful for the treatment of autoimmune and inflammatory diseases such as MS. However, the underlying mechanisms by which HDACs influence immune-mediated diseases such as MS are unclear. More importantly, the question of which specific HDAC(s) are suitable drug targets for the potential treatment of MS remains unanswered. Here, we investigate the functional role of HDAC11 in experimental autoimmune encephalomyelitis, a mouse model for MS. Our results indicate that the loss of HDAC11 in KO mice significantly reduces clinical severity and demyelination of the spinal cord in the post-acute phase of experimental autoimmune encephalomyelitis. The absence of HDAC11 leads to reduced immune cell infiltration into the CNS and decreased monocytes and myeloid DCs in the chronic progressive phase of the disease. Mechanistically, HDAC11 controls the expression of the pro-inflammatory chemokine C–C motif ligand 2 (CCL2) gene by enabling the binding of PU.1 transcription factor to the CCL2 promoter. Our results reveal a novel pathophysiological function for HDAC11 in CNS demyelinating diseases, and warrant further investigations into the potential use of HDAC11-specific inhibitors for the treatment of chronic progressive MS.

scholarly journals Using Experimental  Autoimmune Encephalomyelitis to Identify Prospective Treatments for Multiple Sclerosis

2021 ◽  
Author(s):  
◽  
David O'Sullivan
Keyword(s):  
Multiple Sclerosis ◽  
Macrophage Activation ◽  
Immune Cell ◽  
Mechanisms Of Action ◽  
Autoimmune Encephalomyelitis ◽  
Ifn Γ ◽  
And Migration ◽  
Experimental Autoimmune ◽  
Proliferation And Migration

<p>Multiple sclerosis (MS) is an inflammatory disease, mediated by immune cells attacking the myelin sheaths that surround nerve axons. The autoimmune nature of this disease combined with heterogeneity in disease presentation and pathology makes MS a difficult disease to treat. Although some treatment options are currently available, there is strong demand for more effective treatment alternatives. Therefore, this thesis utilises an animal model of MS, experimental autoimmune encephalomyelitis (EAE), to identify new treatment strategies for MS. These studies encompass three separate lines of inquiry with the primarily focus on investigating the use and mechanisms of action by which microtubule-stabilising drugs (MSDs) modify EAE expression. Two other distinct and novel immunotherapies were also explored: the anti-psychotic drug, risperidone, and the Toll like receptor-9 and nucleotide oligomerization domain-containing protein 2 (TLR-9/NOD2) agonist, MIS416. MSDs are a class of anti-proliferative compounds, which can delay EAE disease onset and reduce disease burden. Administration of the MSD, paclitaxel, directly after EAE immunisation resulted in complete inhibition of antigen-specific encephalogenic responses within the spleen and attenuated responses within the lymph nodes. In contrast, administration of paclitaxel at a later time point did not alter antigen-specific responses, but inhibited immune cell infiltration into the central nervous system (CNS). Using in vivo proliferation and migration assays it was demonstrated that paclitaxel inhibited both immune cell proliferation and migration; indicating these two factors are likely to contribute to the disease modifying effects of MSDs. Futhermore, the combined administration of two MSDs, peloruside A and ixabepilone, resulted in synergistic disease suppression in vivo while the combination of paclitaxel and a currently used MS therapeutic, glatiramer acetate, also exhibited synergistic EAE suppression. Risperidone is an atypical antipsychotic used to treat schizophrenia, however there is evidence that risperidone can also modulate the immune system. The current study demonstrated that risperidone reduced EAE disease severity and induced an increase in splenic CD4⁺ T cells and antigen-specific IFN-γ production. Additionally, as macrophages have a crucial role in EAE disease development, the effect of risperidone on macrophage activation was explored. In cultured macrophages risperidone induced a reduction in IL-12 production and CD40 expression while increasing IL-10 production. These findings suggest that regulation of macrophage activation may contribute to the reduction in EAE. MIS416 is a novel microparticle that stimulates TLR9 and NOD2 receptors. A phase 2A trial is currently underway to evaluate the effects of MIS416 in progressive MS patients, yet the mechanisms by which MIS416 alters the immune system are not completely understood. The current study found that MIS416 effectively but transiently reduces EAE and that IFN-γ is necessary for this disease reduction. These experiments demonstrate that EAE is an appropriate model to further explore the precise mechanisms of action of MIS416. In summary, the work conducted in this thesis has identified the potential of three separate approaches to modify inflammatory disease processes in an animal model of MS. This research provides an initial foundation from which further research can be conducted, with the ultimate goal of developing new treatments for MS.</p>

scholarly journals Regulation of Immune Cell Infiltration into the CNS by Regional Neural Inputs Explained by the Gate Theory

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yasunobu Arima ◽  
Daisuke Kamimura ◽  
Lavannya Sabharwal ◽  
Moe Yamada ◽  
Hidenori Bando ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Cancer Metastasis ◽  
Immune Cell ◽  
Immune Cell Infiltration ◽  
Virus Infections ◽  
Autoimmune Encephalomyelitis ◽  
Mechanical Disruption ◽  
The Central Nervous System ◽  
Experimental Autoimmune

The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a “gateway” at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases.

scholarly journals IC100: A Novel Anti-Asc Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

2020 ◽  
Author(s):  
Haritha L Desu ◽  
Melanie Plastini ◽  
Placido Illiano ◽  
Helen M Bramlett ◽  
W. Dalton Dietrich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
Promising Target ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC-/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. Methods We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30 and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.Results We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. Conclusions These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

scholarly journals Ic100: A Novel Anti-ASC Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

2020 ◽  
Author(s):  
Haritha L Desu ◽  
Melanie Plastini ◽  
Placido Illiano ◽  
Helen M Bramlett ◽  
W. Dalton Dietrich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
Promising Target ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC -/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS.Methods We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55 ). Mice were treated with vehicle or increasing doses of IC100 (10, 30 and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.Results We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4 + and CD8 + T cells and CD11b + MHCII + activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia.Conclusions These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

scholarly journals Using Experimental  Autoimmune Encephalomyelitis to Identify Prospective Treatments for Multiple Sclerosis

2021 ◽  
Author(s):  
◽  
David O'Sullivan
Keyword(s):  
Multiple Sclerosis ◽  
Macrophage Activation ◽  
Immune Cell ◽  
Mechanisms Of Action ◽  
Autoimmune Encephalomyelitis ◽  
Ifn Γ ◽  
And Migration ◽  
Experimental Autoimmune ◽  
Proliferation And Migration

<p>Multiple sclerosis (MS) is an inflammatory disease, mediated by immune cells attacking the myelin sheaths that surround nerve axons. The autoimmune nature of this disease combined with heterogeneity in disease presentation and pathology makes MS a difficult disease to treat. Although some treatment options are currently available, there is strong demand for more effective treatment alternatives. Therefore, this thesis utilises an animal model of MS, experimental autoimmune encephalomyelitis (EAE), to identify new treatment strategies for MS. These studies encompass three separate lines of inquiry with the primarily focus on investigating the use and mechanisms of action by which microtubule-stabilising drugs (MSDs) modify EAE expression. Two other distinct and novel immunotherapies were also explored: the anti-psychotic drug, risperidone, and the Toll like receptor-9 and nucleotide oligomerization domain-containing protein 2 (TLR-9/NOD2) agonist, MIS416. MSDs are a class of anti-proliferative compounds, which can delay EAE disease onset and reduce disease burden. Administration of the MSD, paclitaxel, directly after EAE immunisation resulted in complete inhibition of antigen-specific encephalogenic responses within the spleen and attenuated responses within the lymph nodes. In contrast, administration of paclitaxel at a later time point did not alter antigen-specific responses, but inhibited immune cell infiltration into the central nervous system (CNS). Using in vivo proliferation and migration assays it was demonstrated that paclitaxel inhibited both immune cell proliferation and migration; indicating these two factors are likely to contribute to the disease modifying effects of MSDs. Futhermore, the combined administration of two MSDs, peloruside A and ixabepilone, resulted in synergistic disease suppression in vivo while the combination of paclitaxel and a currently used MS therapeutic, glatiramer acetate, also exhibited synergistic EAE suppression. Risperidone is an atypical antipsychotic used to treat schizophrenia, however there is evidence that risperidone can also modulate the immune system. The current study demonstrated that risperidone reduced EAE disease severity and induced an increase in splenic CD4⁺ T cells and antigen-specific IFN-γ production. Additionally, as macrophages have a crucial role in EAE disease development, the effect of risperidone on macrophage activation was explored. In cultured macrophages risperidone induced a reduction in IL-12 production and CD40 expression while increasing IL-10 production. These findings suggest that regulation of macrophage activation may contribute to the reduction in EAE. MIS416 is a novel microparticle that stimulates TLR9 and NOD2 receptors. A phase 2A trial is currently underway to evaluate the effects of MIS416 in progressive MS patients, yet the mechanisms by which MIS416 alters the immune system are not completely understood. The current study found that MIS416 effectively but transiently reduces EAE and that IFN-γ is necessary for this disease reduction. These experiments demonstrate that EAE is an appropriate model to further explore the precise mechanisms of action of MIS416. In summary, the work conducted in this thesis has identified the potential of three separate approaches to modify inflammatory disease processes in an animal model of MS. This research provides an initial foundation from which further research can be conducted, with the ultimate goal of developing new treatments for MS.</p>

scholarly journals Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination

2018 ◽  
Vol 115 (24) ◽  
pp. 6291-6296 ◽  
Author(s):  
Hawra Karim ◽  
Sung Hoon Kim ◽  
Andrew S. Lapato ◽  
Norio Yasui ◽  
John A. Katzenellenbogen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Immune Cell ◽  
Peripheral Inflammation ◽  
Immune Mechanism ◽  
Autoimmune Encephalomyelitis ◽  
Cytokines And Chemokines ◽  
Cell Accumulation ◽  
Experimental Autoimmune

Estrogen receptor β (ERβ) ligands promote remyelination in mouse models of multiple sclerosis. Recent work using experimental autoimmune encephalomyelitis (EAE) has shown that ERβ ligands induce axon remyelination, but impact peripheral inflammation to varying degrees. To identify if ERβ ligands initiate a common immune mechanism in remyelination, central and peripheral immunity and pathology in mice given ERβ ligands at peak EAE were assessed. All ERβ ligands induced differential expression of cytokines and chemokines, but increased levels of CXCL1 in the periphery and in astrocytes. Oligodendrocyte CXCR2 binds CXCL1 and has been implicated in normal myelination. In addition, despite extensive immune cell accumulation in the CNS, all ERβ ligands promoted extensive remyelination in mice at peak EAE. This finding highlights a component of the mechanism by which ERβ ligands mediate remyelination. Hence, interplay between the immune system and central nervous system may be responsible for the remyelinating effects of ERβ ligands. Our findings of potential neuroprotective benefits arising from the presence of CXCL1 could have implications for improved therapies for multiple sclerosis.

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