scholarly journals Transcriptome analysis of the NR1H3 mouse model of multiple sclerosis reveals a pro-inflammatory phenotype with dysregulation of lipid metabolism and immune response genes

2021 ◽  
Author(s):  
Carles Vilarino-Guell ◽  
Mary Encarnacion ◽  
Cecily Q Bernales ◽  
Emily Kamma ◽  
Pierre Becquart ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Immune System ◽  
Mouse Model ◽  
Transcriptome Analysis ◽  
Human Disease ◽  
Enrichment Analysis ◽  
Wild Type ◽  
Brain And Spinal Cord

Background: The development of effective treatments for multiple sclerosis (MS), and in particular its progressive forms, is hampered by the lack of etiologically relevant cellular and animal models of human disease. Models that recapitulate the biological and pathological processes leading to the onset and progression of MS in patients are likely to afford better translational efficacy. Following the discovery of the NR1H3 p.Arg415Gln pathogenic mutation for progressive MS in two Canadian families, we developed a knock-in mouse model harboring a homologous mutation in the endogenous gene to provide a more physiologically relevant model of human MS. Methods: Gene expression was evaluated in constitutive heterozygote (which recapitulates the human disease genotype) and homozygote Nr1h3 p.Arg413Gln knock-in mice on a C57BL/6 background, and compared to wild-type littermates. AmpliSeq Transcriptome Mouse Gene Expression kits analyzed on an Ion Proton sequencer were used to generate the gene expression profiles of spleen, liver, brain and spinal cord tissue from three-month-old male and female mice. Differential expression between genotypes was assessed with DESeq2, and Gene Ontologies pathways enrichment analysis performed with DAVID v6.8. Benjamini-Hochberg false discovery rate (FDR) correction for multiple testing was applied. Results: Transcriptome analysis of spleen tissue from Nr1h3 p.Arg413Gln mice revealed 23 significantly dysregulated genes (FDR<0.05) with greater than a two-fold change in expression. These include CD5 antigen-like (Cd5l), complement component 6 (C6), procollagen C-endopeptidase enhancer 2 (Pcolce2), interleukin 22 receptor, alpha 2 (Il22ra2), and T cell immunoglobulin and mucin domain containing 4 (Timd4). Gene Ontology enrichment analysis support upregulation of cell cycle pathways and downregulation of immune system response in splenic cells. The liver transcriptome identified 27 significantly dysregulated genes with greater than a two-fold change in expression compared to wild-type littermates. Cd5l, Timd4, C-C motif chemokine receptor 3 (Ccr3), ADAM metallopeptidase domain 11 (Adam11) and macrophage expressed 1 (Mpeg1) were amongst those most significantly dysregulated. Enrichment analysis supported altered immune function with upregulation of sterol and steroid metabolic processes and downregulation of fatty acid biosynthesis and inflammatory and immune system responses. Although brain and spinal cord transcriptome profiles identified several genes significantly dysregulated in Nr1h3 mice compared to wild-type littermates (FDR<0.05), none presented greater than two-fold changes in gene expression. Discussion: The analysis of the Nr1h3 p.Arg413Gln mouse model of MS suggests that the predominance of a pro-inflammatory over a healing or reparative phenotype, combined with deficiencies in myelination and remyelination, are the biological mechanisms implicated in the onset of MS and the development of a more severe progressive disease course observed in patients with NR1H3 mutations. Association of NR1H3 common variants with MS risk indicates that the disruption of these biological and immunological processes is not only informative for familial forms of disease but MS patients at large. Differences in transcriptome profiles underline the value of this model for the development and validation of novel therapeutic strategies and ultimately treatments with the potential to delay or even halt the onset of progressive MS and to ameliorate the severity of clinical symptoms.

scholarly journals Characterization of microglial transcriptomes in the brain and spinal cord of mice in early and late experimental autoimmune encephalomyelitis using a RiboTag strategy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shaona Acharjee ◽  
Paul M. K. Gordon ◽  
Benjamin H. Lee ◽  
Justin Read ◽  
Matthew L. Workentine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Expression Patterns ◽  
Immune Functions ◽  
Autoimmune Encephalomyelitis ◽  
Transcriptional Changes ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Experimental Autoimmune

AbstractMicroglia play an important role in the pathogenesis of multiple sclerosis and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). To more fully understand the role of microglia in EAE we characterized microglial transcriptomes before the onset of motor symptoms (pre-onset) and during symptomatic EAE. We compared the transcriptome in brain, where behavioral changes are initiated, and spinal cord, where damage is revealed as motor and sensory deficits. We used a RiboTag strategy to characterize ribosome-bound mRNA only in microglia without incurring possible transcriptional changes after cell isolation. Brain and spinal cord samples clustered separately at both stages of EAE, indicating regional heterogeneity. Differences in gene expression were observed in the brain and spinal cord of pre-onset and symptomatic animals with most profound effects in the spinal cord of symptomatic animals. Canonical pathway analysis revealed changes in neuroinflammatory pathways, immune functions and enhanced cell division in both pre-onset and symptomatic brain and spinal cord. We also observed a continuum of many pathways at pre-onset stage that continue into the symptomatic stage of EAE. Our results provide additional evidence of regional and temporal heterogeneity in microglial gene expression patterns that may help in understanding mechanisms underlying various symptomology in MS.

Polyamine supplementation in infant formula: Influence on lymphocyte populations and immune system-related gene expression in a Balb/cOlaHsd mouse model

2014 ◽  
Vol 59 ◽  
pp. 8-15 ◽  
Author(s):  
Carlos Gómez-Gallego ◽  
Rafael Frias ◽  
Gaspar Pérez-Martínez ◽  
María José Bernal ◽  
María Jesús Periago ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune System ◽  
Mouse Model ◽  
Infant Formula ◽  
Related Gene ◽  
Lymphocyte Populations

scholarly journals Neuroprotective effect of melatonin in mice with toxic cuprizone model of demyelination and possible pathways of its realization

2018 ◽  
Vol 6 (2) ◽  
Author(s):  
I. Labunets ◽  
A. Rodnichenko ◽  
N. Melnyk ◽  
N. Utko
Keyword(s):  
Spinal Cord ◽  
Immune System ◽  
Glutathione Peroxidase ◽  
Glutathione Reductase ◽  
Neuroprotective Effect ◽  
Nissl Staining ◽  
Spinal Cord Neurons ◽  
Malondialdehyde Content ◽  
Brain And Spinal Cord ◽  
The Brain

The search for tools that increase the effectiveness of cell therapy of demyelinating pathology is relevant. They may be preparations that affect the pathogenetic factors of this pathology, in particular, the pineal hormone melatonin.The purpose of the work is to evaluate the involvement of immune system and antioxidant defense in the implementation of the protective effects of melatonin on morpho-functional disorders in the central nervous system induced by neurotoxin cuprizone.Materials and methods. The toxic demyelination model was induced on 129/Sv mice at the age of 3-5 months by adding cuprizone to food for 3 weeks. Since the 7th day of cuprizone administration, melatonin was injected intraperitoneally at 18:00 daily, at a dose of 1 mg/kg. In the brain of mice, the proportion of CD3+, Nestin+ cells and phagocytic macrophages, the content of malondialdehyde and the activity of antioxidant enzymes was determined. Blood serum was tested for thymic hormone thymulin levels. In the animals, we evaluated the structure of the brain and spinal cord neurons by Nissl staining of histological sections as well as analyzed behavioural reactions in the "open field" test.Results. In the brain of the mice received cuprizone, the proportion of CD3+ and Nestin+ cells, active macrophages and malondialdehyde content increases, glutathione peroxidase and glutathione reductase levels decreases. In the brain and spinal cord of the mice with a cuprizone diet, the proportion of altered neurons increases, and motor and emotional activity decreases. The introduction of melatonin results in a decrease in the relative number of CD3+ cells, active macrophages and malondialdehyde content, increased activity of glutathione peroxidase, glutathione reductase and level of thymulin. In such mice, the proportion of unchanged neurons increases as the number of Nestin+ cells decreases and behavioural responses are also improved.Conclusions. The neuroprotective effect of melatonin in demyelinating pathology is realized through the factors of the immune system and oxidative stress. The results may be useful in the development of new biotechnological approaches to the treatment of demyelinating pathology, in particular, multiple sclerosis.

scholarly journals Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis

1999 ◽  
Vol 66 (3) ◽  
pp. 323-330 ◽  
Author(s):  
C. Liu ◽  
S. Edwards ◽  
Q. Gong ◽  
N. Roberts ◽  
L. D Blumhardt
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Three Dimensional ◽  
Spinal Cord Atrophy ◽  
Brain And Spinal Cord

Detection ofmsj-1 gene expression in the frog,Rana esculenta testis, brain, and spinal cord

2004 ◽  
Vol 68 (2) ◽  
pp. 149-158 ◽  
Author(s):  
Rosaria Meccariello ◽  
Gilda Cobellis ◽  
Donatella Scarpa ◽  
Giulia Fienga ◽  
Riccardo Pierantoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Rana Esculenta ◽  
Brain And Spinal Cord

scholarly journals Mrp1 is Essential for Sphingolipid Signaling to P-Glycoprotein in Mouse Blood–Brain and Blood–Spinal Cord Barriers

2012 ◽  
Vol 33 (3) ◽  
pp. 381-388 ◽  
Author(s):  
Tara A Cartwright ◽  
Christopher R Campos ◽  
Ronald E Cannon ◽  
David S Miller
Keyword(s):  
Spinal Cord ◽  
Endothelial Cells ◽  
Transport Activity ◽  
Wild Type ◽  
Mouse Blood ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Tnf Α ◽  
Glycoprotein Transport ◽  
Brain And Spinal Cord

At the blood–brain and blood–spinal cord barriers, P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to central nervous system (CNS) pharmacotherapy. Recently, we showed that signaling through tumor necrosis factor-α (TNF-α), sphingolipids, and sphingosine-1-phosphate receptor 1 (S1PR1) rapidly and reversibly reduced basal P-glycoprotein transport activity in the rat blood–brain barrier. The present study extends those findings to the mouse blood–brain and blood–spinal cord barriers and, importantly, identifies multidrug resistance-associated protein 1 (Mrp1, Abcc1) as the transporter that mediates S1P efflux from brain and spinal cord endothelial cells. In brain and spinal cord capillaries isolated from wild-type mice, TNF-α, sphingosine, S1P, the S1PR agonist fingolimod (FTY720), and its active, phosphorylated metabolite, FTY720P, reduced P-glycoprotein transport activity; these effects were abolished by a specific S1PR1 antagonist. In brain and spinal cord capillaries isolated from Mrp1-null mice, neither TNF-α nor sphingosine nor FTY720 reduced P-glycoprotein transport activity. However, S1P and FTY720P had the same S1PR1-dependent effects on transport activity as in capillaries from wild-type mice. Thus, deletion of Mrp1 alone terminated endogenous signaling to S1PR1. These results identify Mrp1 as the transporter essential for S1P efflux from the endothelial cells and thus for inside-out S1P signaling to P-glycoprotein at the blood–brain and blood–spinal cord barriers.

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