scholarly journals Unexpected Microglial “De-activation” Associated With Altered Synaptic Transmission in the Early Stages of an Animal Model of Multiple Sclerosis

2019 ◽  
Vol 13 ◽  
pp. 117906951982588 ◽  
Author(s):  
Shaona Acharjee ◽  
Quentin J Pittman
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Basolateral Amygdala ◽  
Demyelinating Disease ◽  
Unexpected Finding ◽  
Autoimmune Encephalomyelitis ◽  
Functional Changes ◽  
Functional Relevance ◽  
Underlying Mechanisms ◽  
Excitatory Drive

Multiple sclerosis, and its animal model—experimental autoimmune encephalomyelitis (EAE), is a demyelinating disease causing motor and sensory dysfunction, as well as behavioral comorbidities. In exploring possible functional changes underlying behavioral comorbidities in EAE, we observed increased excitatory drive onto the major cells of the basolateral amygdala. This was associated with increased numbers of dendritic spines. An unexpected finding was that microglial cells at this time were in a “deactivated” state, and further studies suggested that the microglial deactivation was responsible for the increased excitatory drive. This is the first report of microglial deactivation in an inflammatory disease and raises many questions as to the underlying mechanisms and functional relevance.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

scholarly journals A Pathogenic Role for Myelin-Specific Cd8+ T Cells in a Model for Multiple Sclerosis

2001 ◽  
Vol 194 (5) ◽  
pp. 669-676 ◽  
Author(s):  
Eric S. Huseby ◽  
Denny Liggitt ◽  
Thea Brabb ◽  
Bryan Schnabel ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Demyelinating Disease ◽  
Clinical Symptoms ◽  
Autoimmune Encephalomyelitis ◽  
Effector Cells ◽  
Cns Autoimmunity ◽  
The Central Nervous System

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4+ and CD8+ T cells. Studies of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, focus on the contribution of CD4+ myelin-specific T cells. The role of CD8+ myelin-specific T cells in mediating EAE or MS has not been described previously. Here, we demonstrate that myelin-specific CD8+ T cells induce severe CNS autoimmunity in mice. The pathology and clinical symptoms in CD8+ T cell–mediated CNS autoimmunity demonstrate similarities to MS not seen in myelin-specific CD4+ T cell–mediated EAE. These data suggest that myelin-specific CD8+ T cells could function as effector cells in the pathogenesis of MS.

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 Environmental enrichment alleviates the deleterious effects of stress in experimental autoimmune encephalomyelitis

2020 ◽  
Vol 6 (4) ◽  
pp. 205521732095980
Author(s):  
Antoine Philippe Fournier ◽  
Erwan Baudron ◽  
Isabelle Wagnon ◽  
Philippe Aubert ◽  
Denis Vivien ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Environmental Enrichment ◽  
Acute Stress ◽  
Stressful Events ◽  
Autoimmune Encephalomyelitis ◽  
Relapsing Remitting ◽  
Multiple Sclerosis Patients ◽  
Experimental Autoimmune

Background Clinical observations support the hypothesis that stressful events increase relapse occurrence in multiple sclerosis patients, while stress-reduction strategies can modulate this effect. However, a direct cause-effect relationship between stress level and relapse cannot be firmly established from these data. Objectives The purpose of this work was to address whether modulation of stress could interfere with symptom relapse in an animal model of multiple sclerosis with relapsing-remitting course. Methods Mice bred in standard or enriched environment were subjected to repeated acute stress during the remission phase of relapsing-remitting PLP-induced experimental autoimmune encephalomyelitis. Results We report that repeated acute stress induced a twofold increase in relapse incidence in experimental autoimmune encephalomyelitis. On the other hand, environmental enrichment reduced relapse incidence and severity, and reversed the effects of repeated acute stress. Conclusion These data provide the platform for further studies on the biological processes that link stress and multiple sclerosis relapses in a suitable animal model.

Mesenchymal stem cells as a treatment for multiple sclerosis: a focus on experimental animal studies

2020 ◽  
Vol 31 (2) ◽  
pp. 161-179 ◽  
Author(s):  
Ahmed Lotfy ◽  
Nourhan S. Ali ◽  
Mai Abdelgawad ◽  
Mohamed Salama
Keyword(s):  
Multiple Sclerosis ◽  
Stem Cells ◽  
Animal Model ◽  
Mesenchymal Stem Cells ◽  
Animal Studies ◽  
Culture Medium ◽  
Therapeutic Effects ◽  
Autoimmune Encephalomyelitis ◽  
Main Factors ◽  
Experimental Autoimmune

AbstractMultiple sclerosis (MS) is a progressive and debilitating neurological condition in which the immune system abnormally attacks the myelin sheath insulating the nerves. Mesenchymal stem cells (MSCs) are found in most adult tissues and play a significant systemic role in self-repair. MSCs have promising therapeutic effects in many diseases, such as autoimmune diseases, including MS. MSCs have been tested in MS animal models, such as experimental autoimmune encephalomyelitis. Other studies have combined other agents with MSCs, genetically modified MSCs, or used culture medium from MSCs. In this review, we will summarize these studies and compare the main factors in each study, such as the source of MSCs, the type of animal model, the route of injection, the number of injected cells, and the mechanism of action.

Role of Gut Microbiota in Multiple Sclerosis and Potential Therapeutic Implications

2021 ◽  
Vol 19 ◽  
Author(s):  
Xu Wang ◽  
Zhen Liang ◽  
Shengnan Wang ◽  
Di Ma ◽  
Mingqin Zhu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Gut Microbiota ◽  
Demyelinating Disease ◽  
Inflammatory Diseases ◽  
Intestinal Barrier ◽  
Autoimmune Response ◽  
Therapeutic Implications ◽  
The Central Nervous System ◽  
Underlying Mechanisms

: The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on the gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota has also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

scholarly journals Virus Persistence in an Animal Model of Multiple Sclerosis Requires Virion Attachment to Sialic Acid Coreceptors

2004 ◽  
Vol 78 (16) ◽  
pp. 8860-8867 ◽  
Author(s):  
A. S. Manoj Kumar ◽  
Honey V. Reddi ◽  
Aisha Y. Kung ◽  
Mauro Dal Canto ◽  
Howard L. Lipton
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Sialic Acid ◽  
Demyelinating Disease ◽  
Direct Role ◽  
Virus Persistence ◽  
Sialic Acid Binding ◽  
Relevant Animal Model ◽  
Encephalomyelitis Virus ◽  
The Central Nervous System

ABSTRACT Persistent Theiler's virus infection in the central nervous system (CNS) of mice provides a highly relevant animal model for multiple sclerosis. The low-neurovirulence DA strain uses sialic acid as a coreceptor for cell binding before establishing infection. During adaptation of DA virus to growth in sialic acid-deficient cells, three amino acid substitutions (G1100D, T1081I, and T3182A) in the capsid arose, and the virus no longer used sialic acid as a coreceptor. The adapted virus retained acute CNS virulence, but its persistence in the CNS, white matter inflammation, and demyelination were largely abrogated. Infection of murine macrophage but not oligodendrocyte cultures with the adapted virus was also significantly reduced. Substitution of G1100D in an infectious DA virus cDNA clone demonstrated a major role for this mutation in loss of sialic acid binding and CNS persistence. These data indicate a direct role for sialic acid binding in Theiler's murine encephalomyelitis virus persistence and chronic demyelinating disease.

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