scholarly journals Lowering blood cholesterol does not affect neuroinflammation in experimental autoimmune encephalomyelitis

2021 ◽  
Author(s):  
solenne vigne ◽  
Donovan Duc ◽  
Yannick Yersin ◽  
Jessica Rebeaud ◽  
Florian Ruiz ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Cholesterol Level ◽  
Blood Cholesterol ◽  
Lipid Lowering ◽  
Blood Levels ◽  
Disease Course ◽  
Blood Cholesterol Level ◽  
Autoimmune Encephalomyelitis ◽  
The Impact ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. Metabolic syndrome (MetS) including dyslipidemia has been associated with a worse outcome in MS disease. Furthermore, the lipid lowering drugs statins have been proposed to improve MS disease course. However, cholesterol is also rate-limiting for myelin biogenesis and promotes remyelination in MS animal models. Thus, the impact of circulating blood cholesterol level during the disease remains debated and controversial. Methods: We assessed the role of circulating cholesterol on the murine model of MS, the experimental autoimmune encephalomyelitis (EAE) disease using two different approaches: 1) the mouse model of familial hypercholesterolemia induced by low density lipoprotein receptor (LDLr) deficiency, and 2) the use of the monoclonal anti-PCSK9 neutralizing antibody alirocumab which reduces LDLr degradation and consequently lowers blood levels of cholesterol. Results: Elevated blood cholesterol levels induced by LDLr deficiency did not worsen clinical symptoms of mice during EAE. In addition, we observed that the anti-PCSK9 antibody alirocumab did not influence EAE disease course, nor modulate the immune response in EAE. Conclusions: These findings suggest that blood cholesterol level has no direct role in neuro-inflammatory diseases and that the previously shown protective effects of statins in MS are not related to circulating cholesterol.

Immunoglobulins Treatment in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2000 ◽  
Vol 6 (2_suppl) ◽  
pp. S6-S8 ◽  
Author(s):  
Anat Achiron ◽  
Shmuel Miron
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Mechanisms Of Action ◽  
Treatment Modalities ◽  
Future Research ◽  
Disease Course ◽  
Immunomodulatory Effects ◽  
Duration Of Treatment ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Intravenously administered immunoglobulins (IgG) treatment has several modes of action that can regulate the immune response during different steps of the inflammatory process in experimental autoimmune encephalomyelitis (EAE) and Multiple Sclerosis (MS). The immunomodulatory effects IgG are largely dependent on their ability to interact with membrane molecules of lymphocytes and monocytes. Better understanding of these mechanisms of action in relation to the pathogenesis of MS, is important in order to decide the time of initiation and the duration of treatment in MS patients. In order to have the best beneficial effect on disease course, future research should focus on the initial events that activate the disease and on the early treatment modalities of IgG in MS.

Effect of 10-day forced treadmill training on neurotrophic factors in experimental autoimmune encephalomyelitis

2013 ◽  
Vol 38 (2) ◽  
pp. 194-199 ◽  
Author(s):  
Darpan I. Patel ◽  
Lesley J. White
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Progression ◽  
Wheel Running ◽  
Treadmill Running ◽  
Clinical Effects ◽  
Control Groups ◽  
Autoimmune Encephalomyelitis ◽  
Tnf Α ◽  
The Impact ◽  
Experimental Autoimmune

The impact of exercise on disease progression in multiple sclerosis (MS) is unclear. In the present study, we evaluated the clinical effects of forced wheel running on rats induced with experimental autoimmune encephalomyelitis (EAE), a model of MS. Female Lewis rats (n = 40) were randomly assigned to 1 of 4 groups prior to inoculation: EAE exercise (EAE-Ex), EAE sedentary (EAE-Sed), control exercise (Con-Ex), or control sedentary (Con-Sed). Exercise training was composed of forced treadmill running at increasing intensity across 10 consecutive days. No significant differences in clinical disability were observed in the EAE groups at the conclusion of this study. Furthermore, no significant differences in brain mass were observed across groups. Analysis of brain tissue proteins revealed that tumour necrosis factor-α (TNF-α) concentrations were higher in both EAE groups compared with the control groups (p < 0.05); however, no significant differences were seen between the EAE-Ex and EAE-Sed groups. The Con-Ex group had lower whole-brain TNF-α compared with the Con-Sed group (p < 0.05). Nerve growth factor concentrations were greater in the EAE-Ex animals compared with both control groups (p < 0.05 for both). No differences were seen in brain-derived neurotrophic factor. Our results indicate that aerobic exercise can modulate the proteins associated with disability in EAE; however, further research is required to understand the total impact of exercise on EAE disability and disease progression.

scholarly journals Microglial Nox2 Plays a Key Role in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Chih-Fen Hu ◽  
San-Pin Wu ◽  
Gu-Jiun Lin ◽  
Chi-Chang Shieh ◽  
Chih-Sin Hsu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lupus Erythematosus ◽  
Autoimmune Encephalomyelitis ◽  
Chemokine Production ◽  
Phagocyte Nadph Oxidase ◽  
Cytokines And Chemokines ◽  
Gene Ablation ◽  
The Impact ◽  
Experimental Autoimmune

While oxidative stress has been linked to multiple sclerosis (MS), the role of superoxide-producing phagocyte NADPH oxidase (Nox2) in central nervous system (CNS) pathogenesis remains unclear. This study investigates the impact of Nox2 gene ablation on pro- and anti-inflammatory cytokine and chemokine production in a mouse experimental autoimmune encephalomyelitis (EAE) model. Nox2 deficiency attenuates EAE-induced neural damage and reduces disease severity, pathogenic immune cells infiltration, demyelination, and oxidative stress in the CNS. The number of autoreactive T cells, myeloid cells, and activated microglia, as well as the production of cytokines and chemokines, including GM-CSF, IFNγ, TNFα, IL-6, IL-10, IL-17A, CCL2, CCL5, and CXCL10, were much lower in the Nox2−/− CNS tissues but remained unaltered in the peripheral lymphoid organs. RNA-seq profiling of microglial transcriptome identified a panel of Nox2 dependent proinflammatory genes: Pf4, Tnfrsf9, Tnfsf12, Tnfsf13, Ccl7, Cxcl3, and Cxcl9. Furthermore, gene ontology and pathway enrichment analyses revealed that microglial Nox2 plays a regulatory role in multiple pathways known to be important for MS/EAE pathogenesis, including STAT3, glutathione, leukotriene biosynthesis, IL-8, HMGB1, NRF2, systemic lupus erythematosus in B cells, and T cell exhaustion signaling. Taken together, our results provide new insights into the critical functions performed by microglial Nox2 during the EAE pathogenesis, suggesting that Nox2 inhibition may represent an important therapeutic target for MS.

scholarly journals Tim-3 on CD4+ T cells is associated with pathology in experimental autoimmune encephalomyelitis of mouse

2021 ◽  
Vol 19 ◽  
pp. 205873922110301
Author(s):  
Qi Guo
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Immune Checkpoints ◽  
Autoimmune Encephalomyelitis ◽  
Reliable Model ◽  
The Central Nervous System ◽  
The Impact ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is a reliable model to study the pathogenesis of Multiple sclerosis (MS), which is a progressive autoimmune-mediated inflammation of the central nervous system (CNS). Tim-3 is one of the crucial immune checkpoints in immune tolerance. We investigated the impact of Tim3 in EAE by the anti-Tim3 antibody and detected the immune cell and inflammation through flow cytometry and ELISA. In this study we found that CD4 T cells express low levels of Tim-3 in EAE mice. Tim-3 suppression exacerbated the disease progression in EAE mice. Furthermore, the Galectin-9/Tim-3 pathway promoted the apoptosis of CD4 T cells and inhibited the differentiation of Th17 in EAE mice. Our study unravels the anti-inflammatory Galectin-9/Tim-3 pathway in EAE mice and provides a potential therapeutic target for EAE and MS treatment.

scholarly journals Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Luo ◽  
Xianzhen Hu ◽  
Michael L. Dixon ◽  
Brandon J. Pope ◽  
Jonathan D. Leavenworth ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Cns Autoimmunity ◽  
The Impact ◽  
Experimental Autoimmune

Abstract Background Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

scholarly journals Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Louisane Desbiens ◽  
Catherine Lapointe ◽  
Marjan Gharagozloo ◽  
Shaimaa Mahmoud ◽  
Gunnar Pejler ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Score ◽  
Autoimmune Encephalomyelitis ◽  
Mast Cell Protease ◽  
Mouse Mast Cell ◽  
The Impact ◽  
Early Phases ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized withMOG35–55plus complete Freund’s adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

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