scholarly journals Differential Proteomic Analysis of Astrocytes and Astrocytes-Derived Extracellular Vesicles from Control and Rai Knockout Mice: Insights into the Mechanisms of Neuroprotection

2021 ◽  
Vol 22 (15) ◽  
pp. 7933
Author(s):  
Tommaso Montecchi ◽  
Enxhi Shaba ◽  
Domiziana De Tommaso ◽  
Fabrizio Di Giuseppe ◽  
Stefania Angelucci ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Oligodendrocyte Differentiation ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune Encephalomyelitis Mouse ◽  
Alternative Phenotypes ◽  
Proteomic Approach ◽  
Primary Mouse ◽  
The Impact ◽  
And Oxidative Stress ◽  
Experimental Autoimmune

Reactive astrocytes are a hallmark of neurodegenerative disease including multiple sclerosis. It is widely accepted that astrocytes may adopt alternative phenotypes depending on a combination of environmental cues and intrinsic features in a highly plastic and heterogeneous manner. However, we still lack a full understanding of signals and associated signaling pathways driving astrocyte reaction and of the mechanisms by which they drive disease. We have previously shown in the experimental autoimmune encephalomyelitis mouse model that deficiency of the molecular adaptor Rai reduces disease severity and demyelination. Moreover, using primary mouse astrocytes, we showed that Rai contributes to the generation of a pro-inflammatory central nervous system (CNS) microenvironment through the production of nitric oxide and IL-6 and by impairing CD39 activity in response to soluble factors released by encephalitogenic T cells. Here, we investigated the impact of Rai expression on astrocyte function both under basal conditions and in response to IL-17 treatment using a proteomic approach. We found that astrocytes and astrocyte-derived extracellular vesicles contain a set of proteins, to which Rai contributes, that are involved in the regulation of oligodendrocyte differentiation and myelination, nitrogen metabolism, and oxidative stress. The HIF-1α pathway and cellular energetic metabolism were the most statistically relevant molecular pathways and were related to ENOA and HSP70 dysregulation.

scholarly journals Deletion of arginase 2 attenuates neuroinflammation in an experimental model of optic neuritis

PLoS ONE ◽  
2021 ◽  
Vol 16 (3) ◽  
pp. e0247901
Author(s):  
Amritha A. Candadai ◽  
Fang Liu ◽  
Abdelrahman Y. Fouda ◽  
Moaddey Alfarhan ◽  
Chithra D. Palani ◽  
...  
Keyword(s):  
Optic Neuritis ◽  
Experimental Model ◽  
Axonal Degeneration ◽  
Wild Type ◽  
Autoimmune Encephalomyelitis ◽  
Optic Nerves ◽  
Clinical Presentations ◽  
Retinal Neurodegeneration ◽  
The Impact ◽  
Experimental Autoimmune

Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis.

scholarly journals The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 748 ◽  
Author(s):  
Gabriele Di Sante ◽  
Susanna Amadio ◽  
Beatrice Sampaolese ◽  
Maria Elisabetta Clementi ◽  
Mariagrazia Valentini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Clinical Score ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune Encephalomyelitis Mouse ◽  
Extracellular Signaling ◽  
Relapsing Remitting ◽  
Inflammatory Processes ◽  
Experimental Autoimmune

S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

scholarly journals Impact of High Intensity Exercise on Muscle Morphology in EAE Rats

2015 ◽  
pp. 907-923 ◽  
Author(s):  
I. WENS ◽  
U. DALGAS ◽  
K. VERBOVEN ◽  
L. KOSTEN ◽  
A. STEVENS ◽  
...  
Keyword(s):  
Muscle Fiber ◽  
High Intensity ◽  
High Intensity Exercise ◽  
Muscle Performance ◽  
Autoimmune Encephalomyelitis ◽  
Cross Sectional ◽  
Muscle Work ◽  
General Exercise ◽  
The Impact ◽  
Experimental Autoimmune

The impact of high-intensity exercise on disease progression and muscle contractile properties in experimental autoimmune encephalomyelitis (EAE) remains unclear. Control (CON) and EAE rats were divided into sedentary and exercise groups. Before onset (experiment 1, n=40) and after hindquarter paralysis (experiment 2, n=40), isokinetic foot extensor strength, cross sectional area (CSA) of tibialis anterior (TA), extensor digitorum longus (EDL) and soleus (SOL) and brain-derived neurotrophic factor (BDNF) levels were assessed. EAE reduced muscle fiber CSA of TA, EDL and SOL. In general, exercise was not able to affect CSA, whereas it delayed hindquarter paralysis peak. CON muscle work peaked and declined, while it remained stable in EAE. BDNF-responses were not affected by EAE or exercise. In conclusion, EAE affected CSA-properties of TA, EDL and SOL, which could, partly, explain the absence of peak work during isokinetic muscle performance in EAE-animals. However, exercise was not able to prevent muscle fiber atrophy.

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.

scholarly journals Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yanan Chen ◽  
Rejani B Kunjamma ◽  
Molly Weiner ◽  
Jonah R Chan ◽  
Brian Popko
Keyword(s):  
Stress Response ◽  
Combined Treatment ◽  
Integrated Stress Response ◽  
Oligodendrocyte Differentiation ◽  
Autoimmune Encephalomyelitis ◽  
Inflammatory Lesions ◽  
Myelin Thickness ◽  
Ifn Γ ◽  
Cns Delivery ◽  
Experimental Autoimmune

The inflammatory environment of demyelinated lesions in multiple sclerosis (MS) patients contributes to remyelination failure. Inflammation activates a cytoprotective pathway, the integrated stress response (ISR), but it remains unclear whether enhancing the ISR can improve remyelination in an inflammatory environment. To examine this possibility, the remyelination stage of experimental autoimmune encephalomyelitis (EAE), as well as a mouse model that incorporates cuprizone-induced demyelination along with CNS delivery of the proinflammatory cytokine IFN-γ were used here. We demonstrate that either genetic or pharmacological ISR enhancement significantly increased the number of remyelinating oligodendrocytes and remyelinated axons in the inflammatory lesions. Moreover, the combined treatment of the ISR modulator Sephin1 with the oligodendrocyte differentiation enhancing reagent bazedoxifene increased myelin thickness of remyelinated axons to pre-lesion levels. Taken together, our findings indicate that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation, suggesting that ISR enhancement may provide reparative benefit to MS patients.

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