Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of mouse experimental autoimmune encephalomyelitis (EAE) from spinal cord preparations of opticospinal EAE (OSE) and MOG-induced EAE

ABSTRACT: Genetic opticospinal EAE (OSE) and MOG-induced EAE (MOG-EAE) are two experimental autoimmune encephalomyelitis (EAE) mouse models of human multiple sclerosis. For the OSE model, double-transgenic 2D2 (TCRMOG) x IgHMOG mice were used. For MOG-EAE, wildtype C57BL/6 mice were immunized with a MOG peptide consisting of the amino acids 35-55, administered in complete Freund’s adjuvant containing 5mg / ml Mycobacterium tuberculosi. The severity of EAE was rated on the scale 0: healthy animal; 1: animal with a flaccid tail; [...]; 4: animal with both hind legs paralyzed. The case groups in the experiment were: OSE1: OSE with disease score 1; OSE4: OSE with disease score 4; MOG4: MOG-EAE injected with both MOG and adjuvant, with disease score 4. The control groups in the experiment were: OSE0: OSE with disease score 0; CFA: C57BL/6 mice injected only with adjuvant (no MOG); WT: Wildtype C57BL/6 mice. The aim of the experiment was to assess gene expression differences 1) between OSE4 and OSE0, 2) between OSE1 and OSE0, and 3) between MOG4 and CFA. For control, WT was compared to OSE0 and CFA. Subsequently, differentially expressed transcripts were compared, first, between the OSE4 vs. OSE0 and the MOG4 vs. CFA contrasts (different EAE models) and, second, between the OSE4 vs. OSE0 and the OSE1 vs. OSE0 contrasts (different EAE severity).

ORGANISM(S): Mus musculus

SUBMITTER: Till Andlauer

PROVIDER: E-MTAB-9132 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The study assessed the efficacy of R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. R-flurbiprofen, also known as tarenflurbil, is the R-enantiomer of the cyclooxyygenase inhibitor S-flurbiprofen. It is ineffective in terms of cyclooxygenase inhibition and has no relevant toxicity in humans. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T-cells, CTLA4+ inhibitory T-cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced (Sentrix6 results). The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R- to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS. To assess effects of R-flurbiprofen on EAE evoked gene regulations in the spinal cord a genome wide expression analysis was performed using Illumina Sentrix 6 v2 BeadChips. For the microarray study female C57BL6/J mice were immunized according to a standard protocol using the Hooke KitM-bM-^DM-" MOG35-55/CFA emulsion PTX (EK-2110, Hooke Labs, St Lawrence, MA), which contains 200 M-BM-5g myelin oligodendrocyte glycoprotein (MOG) 35-55 emulsified in 200 M-BM-5l Complete FreundM-bM-^@M-^Ys Adjuvant (CFA). The emulsion was injected subcutaneously at two sites followed by two intraperitoneal (i.p.) injections of 200 ng pertussis toxin (PTX) in phosphate buffered saline (PBS), the first 1-2 h after MOG35-55, and the second 24 h after MOG35-55. Control mice received CFA without MOG35-55 (sham mice). Treatment with R-flurbiprofen or vehicle (n = 12 per group) was started 5 days after immunization and was administered continuously via the drinking water up to the end. Spinal cords were dissected out during the flare of the disease, day 16 after immunization. For microarray analysis, total RNA was extracted from homogenizedlumbar spinal cord tissue with Trizol reagent, followed by clean-up and DNase I treatment with QIAGEN RNeasy mini kit. RNA quality was checked (Nanodrop ND-1000, Agilent 2100 Bioanalyzer), and subsequently biotinylated and hybridized to Mouse Sentrix-6 V2 Expression BeadChips (Illumina). Each sample consisted of pooled lumbar spinal cord tissue from 3 animals and 3 replicate samples were analyzed per group, i.e. the analysis is based on 9 mice per group. Groups were CFA-control with vehicle treatment, CFA-control with R-flurbiprofen, EAE-vehicle and EAE-R-flurbiprofen treatment. Treatment was started 5 days after immunization. For dissection, pairs were matched according to the clinical scores. QC, labeling, hybridization and raw data evaluation and normalization were done according to standard protocols at the core facilities of the Deutsche Krebsforschungszentrum, Heidelberg, Germany.

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Gene expression profiling of mouse experimental autoimmune encephalomyelitis (EAE) from spinal cord preparations of opticospinal EAE (OSE) and MOG-induced EAE

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