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 Oleacein Attenuates the Pathogenesis of Experimental Autoimmune Encephalomyelitis through Both Antioxidant and Anti-Inflammatory Effects

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1161
Author(s):  
Beatriz Gutiérrez-Miranda ◽  
Isabel Gallardo ◽  
Eleni Melliou ◽  
Isabel Cabero ◽  
Yolanda Álvarez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Proinflammatory Cytokines ◽  
Histological Evaluation ◽  
Autoimmune Encephalomyelitis ◽  
Bv2 Cells ◽  
Bv2 Microglia ◽  
Anti Inflammatory ◽  
The Impact ◽  
Experimental Autoimmune

Oxidative stress and proinflammatory cytokines are factors affecting multiple sclerosis (MS) disease progression. Oleacein (OLE), an olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential application to treat neuroinflammatory disorders. Herein, we investigated the impact of OLE on the main clinic-pathological features of experimental autoimmune encephalomyelitis (EAE), an animal model for MS, including paralysis, demyelination, central nervous system (CNS) inflammation/oxidative stress and blood-brain barrier (BBB) breakdown. Methods: Mice were immunized with the myelin oligodendrocyte glycoprotein peptide, MOG35-55, to induce EAE, and OLE was administrated from immunization day. Serum, optic nerve, spinal cord and cerebellum were collected to evaluate immunomodulatory activities at a systemic level, as well as within the CNS. Additionally, BV2 microglia and the retinal ganglion cell line RGC-5 were used to confirm the direct effect of OLE on CNS-resident cells. Results: We show that OLE treatment effectively reduced clinical score and histological signs typical of EAE. Histological evaluation confirmed a decrease in leukocyte infiltration, demyelination, BBB disruption and superoxide anion accumulation in CNS tissues of OLE-treated EAE mice compared to untreated ones. OLE significantly decreased expression of proinflammatory cytokines (IL-13, TNFα, GM-CSF, MCP-1 and IL-1β), while it increased the anti-inflammatory cytokine IL-10. Serum levels of anti-MOG35-55 antibodies were also lower in OLE-treated EAE mice. Further, OLE significantly diminished the presence of oxidative system parameters, while upregulated the ROS disruptor, Sestrin-3. Mechanistically, OLE prevented NLRP3 expression, phosphorylation of p65-NF-κB and reduced the synthesis of proinflammatory mediators induced by relevant inflammatory stimuli in BV2 cells. OLE did not affect viability or the phagocytic capabilities of BV2 microglia. In addition, apoptosis of RGC-5 induced by oxidative stressors was also prevented by OLE. Conclusion: Altogether, our results show that the antioxidant and anti-inflammatory OLE has neuroprotective effects in the CNS of EAE mice, pointing out this natural product as a candidate to consider for research on MS treatments.

scholarly journals Gelatinase B/matrix metalloproteinase-9 is a phase-specific effector molecule, independent from Fas, in experimental autoimmune encephalomyelitis

2018 ◽  
Author(s):  
Estefania Ugarte-Berzal ◽  
Nele Berghmans ◽  
Lise Boon ◽  
Erik Martens ◽  
Jennifer Vandooren ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Matrix Metalloproteinase ◽  
Autoimmune Encephalomyelitis ◽  
Cytokines And Chemokines ◽  
Remission Phase ◽  
The Brain ◽  
Metalloproteinase 9 ◽  
Single Knockout ◽  
Experimental Autoimmune

AbstractGelatinase B/matrix metalloproteinase-9 (MMP-9) triggers multiple sclerosis (MS) and the animal model of experimental autoimmune encephalomyelitis (EAE) by the breakdown of the blood-brain barrier. Interestingly, MMP-9 is beneficial in systemic autoimmunity caused by Fas-deficiency. Fas-deficient (faslpr)and Fas-ligand-deficient mice are protected against EAE. We here investigated the interaction between Fas and MMP-9 in the setting of induction of EAE and compared short- and long-term effects. We provoked EAE with myelin oligodendrocyte glycoprotein (MOG) peptide and compared EAE development in four genotypes (wild-type (WT), single knockoutmmp-9−/−,faslpr, andmmp-9−/−/faslpr) and monitored leukocytes, cytokines and chemokines as immunological parameters. As expected,faslprmice were resistant against EAE induction, whereas MMP-9 single knockout mice were not. In the doublemmp-9−/−/faslprmice the effects on disease scores pointed to independent rather than interrelated disease mechanisms. On a short term, leukocytes infiltrated into the brain and cytokines and chemokines after EAE induction were significantly higher in all the four genotypes studied, even in thefaslprandmmp9-/-/faslpr, which did not develop clinical disease. The levels of MMP-9 but not of MMP-2 were increased in the brain and in the peripheral organs after EAE induction. After 40 days all the animals recovered and did not show signs of EAE. However, the absence of MMP-9 in the remission phase suggested a protective role of MMP-9 in the late phase of the disease, thus singlemmp-9−/−mice presented a delayed onset and remission in comparison with WT animals suggesting a phase-dependent role of MMP-9 in the disease. Nevertheless, the levels of some cytokines and chemokines were remained higher than in control animals even 100 days after EAE induction, attesting to a prolonged state of immune activation. We thus yielded new insights and useful markers to monitor this activated immune status. Furthermore, MMP-9 but not MMP-2 levels remained increased in the brains and, to a higher extend, in the spleens of the WT mice even during the remission phase, which is in line with the role of MMP-9 as a useful marker and a protective factor for EAE in the remission phase.

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.

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 Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ulaş Ceylan ◽  
Steffen Haupeltshofer ◽  
Laura Kämper ◽  
Justus Dann ◽  
Björn Ambrosius ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Microglial Activation ◽  
Clinical Signs ◽  
Progressive Multiple Sclerosis ◽  
Autoimmune Encephalomyelitis ◽  
Positive Effects ◽  
Markers Of Inflammation ◽  
Experimental Autoimmune

ObjectiveProgressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine in vitro and in chronic experimental autoimmune encephalomyelitis (EAE).MethodsMicroglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry.ResultsIron impaired microglial function in vitro regarding phagocytosis and markers of inflammation; this was regulated by clozapine, reflected in reduced release of IL-6 and normalization of neuronal phagocytosis. In chronic EAE, clozapine dose-dependently attenuated clinical signs and still had an effect if applied in a therapeutic setting. Early mild sedative effects habituated over time. Histologically, demyelination was reduced by clozapine and positive effects on inflammation strongly correlated with reduced iron deposition. This was accompanied by reduced expression of DMT-1, an iron transport protein.ConclusionsClozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

scholarly journals The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators

2021 ◽  
Vol 15 ◽  
Author(s):  
Svetlana Trifunovic ◽  
Ivana Stevanovic ◽  
Ana Milosevic ◽  
Natasa Ristic ◽  
Marija Janjic ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Hpa Axis ◽  
Superoxide Anion ◽  
Adrenal Glands ◽  
Demyelinating Disease ◽  
Unknown Origin ◽  
Autoimmune Encephalomyelitis ◽  
Hypothalamic Pituitary Adrenal ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic–pituitary–adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.

Ncx3 gene ablation impairs oligodendrocyte precursor response and increases susceptibility to experimental autoimmune encephalomyelitis

Glia ◽  
2016 ◽  
Vol 64 (7) ◽  
pp. 1124-1137 ◽  
Author(s):  
Antonella Casamassa ◽  
Claudia La Rocca ◽  
Sophie Sokolow ◽  
Andre Herchuelz ◽  
Giuseppe Matarese ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Gene Ablation ◽  
Oligodendrocyte Precursor ◽  
Experimental Autoimmune
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