Dataset Information

Expression of disease-related miRNAs in white-matter lesions of progressive multiple sclerosis brains.

ABSTRACT:

Background

MicroRNA (miRNA) expression in the serum of multiple sclerosis (MS) patients has been correlated with white matter (WM) magnetic resonance imaging (MRI) abnormalities. The expression levels and cellular specificity of the target genes of these miRNAs are unknown in MS brain.

Objective

The aim of this study was to analyze and validate the expression of miRNAs, previously reported as dysregulated in sera of MS patients, in white-matter lesions (WMLs) of progressive MS brains.

Methods

We performed global miRNA expression profiling analysis in demyelinated WMLs of progressive MS brains (n = 5) and compared the significantly altered miRNAs to previously identified miRNAs from sera of MS patients. Top dysregulated miRNAs common between the two datasets were validated in an independent cohort of MS brains by quantitative PCR (qPCR) and in situ hybridization.

Results

Among the miRNAs that were significantly changed in WML tissues, 11 were similar to pathogenic and 12 were common to protective miRNAs previously identified in sera and correlating with WM MRI abnormalities. Importantly, the expression levels of 58% of the protective miRNAs (7 of 12) were decreased in MS lesions compared to surrounding normal-appearing tissue. Target genes of these miRNAs were also altered in MS lesions and queries of cell-specific databases identified astrocytes and microglia as the key cellular expressers of these genes in MS brains.

Conclusions

We identified miRNAs that correlate with MRI abnormalities in lesioned tissue from MS brains.

SUBMITTER: Tripathi A

PROVIDER: S-EPMC6530016 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Expression of disease-related miRNAs in white-matter lesions of progressive multiple sclerosis brains.

Tripathi Ajai A Volsko Christina C Datta Ushasi U Regev Keren K Dutta Ranjan R

Annals of clinical and translational neurology 20190321 5

<h4>Background</h4>MicroRNA (miRNA) expression in the serum of multiple sclerosis (MS) patients has been correlated with white matter (WM) magnetic resonance imaging (MRI) abnormalities. The expression levels and cellular specificity of the target genes of these miRNAs are unknown in MS brain.<h4>Objective</h4>The aim of this study was to analyze and validate the expression of miRNAs, previously reported as dysregulated in sera of MS patients, in white-matter lesions (WMLs) of progressive MS bra ...[more]

PMID: 31139683

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Project description:Pathogenic or regulatory effects of natural killer (NK) cells are implicated in many autoimmune diseases, but evidence in multiple sclerosis (MS) and its murine models remains equivocal. In an effort to illuminate this, we have here analysed expression of the prototypic NK cell marker, NCR1 (natural cytotoxicity triggering receptor; NKp46; CD335), an activating receptor expressed by virtually all NK cells and therefore considered a pan-marker for NK cells. The only definitive ligand of NCR1 is influenza haemagglutinin, though there are believed to be others. In this study, we investigated whether there were differences in NCR1+ cells in the peripheral blood of MS patients and whether NCR1+ cells are present in white matter lesions.We first investigated the expression of NCR1 on peripheral blood mononuclear cells and found no significant difference between healthy controls and MS patients. We then investigated mRNA levels in central nervous system (CNS) tissue from MS patients: NCR1 transcripts were increased more than 5 times in active disease lesions. However when we performed immunohistochemical staining of this tissue, few NCR1+ NK cells were identified. Rather, the major part of NCR1 expression was localised to astrocytes, and was considerably more pronounced in MS patients than controls. In order to further validate de novo expression of NCR1 in astrocytes, we used an in vitro staining of the human astrocytoma U251 cell line grown to model whether cell stress could be associated with expression of NCR1. We found up-regulation of NCR1 expression in U251 cells at both the mRNA and protein levels.The data presented here show very limited expression of NCR1+ NK cells in MS lesions, the majority of NCR1 expression being accounted for by expression on astrocytes. This is compatible with a role of this cell-type and NCR1 ligand/receptor interactions in the innate immune response in the CNS in MS patients. This is the first report of NCR1 expression on astrocytes in MS tissue: it will now be important to unravel the nature of cellular interactions and signalling mediated through innate receptor expression on astrocytes.

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Dataset Information

Expression of disease-related miRNAs in white-matter lesions of progressive multiple sclerosis brains.

Background

Objective

Methods

Results

Conclusions

Publications

Expression of disease-related miRNAs in white-matter lesions of progressive multiple sclerosis brains.

Similar Datasets

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