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Sulfasalazine alters microglia phenotype by competing endogenous RNA effect of miR-136-5p and long non-coding RNA HOTAIR in cuprizone-induced demyelination.

Abstract：

:Sulfasalazine (SF) promotes remyelination and improves the outcome of multiple sclerosis (MS) patients. However, the underlining mechanism remains elusive. Here, we examined whether SF blocks microglia switching to a pro-inflammatory M1-like phenotype through a competing endogenous RNA (ceRNA) effects in cuprizone-induced demyelination. The microglia reprogramming effects of SF in the mice model of cuprizone-induced demyelination was measured by histological, immunohistochemical and molecular biological methods. We also measured the effects of the condition media from SF-treated microglia on the differentiation of OLN-93 cells. Insights of the mechanism of ceRNAs of miR-136-5p and long non-coding RNA (lncRNA) HOTAIR were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation. Microglia switched to a pro-inflammatory M1-like phenotype in cuprizone induced-demyelination. Conversely, SF inhibited the M1-like polarization with the increased remyelination which was attenuated by microglia depletion. SF inhibited production of M1-like factors TNF-α and INF-γ in microglia, and thereby promoted the differentiation of OLN-93 oligodendrocytes. SF down-regulated lncRNA HOTAIR but up-regulated miR-136-5p, and thus inactivated AKT2-NF-κB in cuprizone-treated microglia. Importantly, lncRNA HOTAIR overexpression reversed the increased miR-136-5p expression by SF and thereby attenuated the inhibition of AKT2-mediated NF-κB activation. Mimic of miR-136-5p inhibited cuprizone-induced activation of AKT2-NF-κB in the microglia. In summary, SF blocks microglia switching to a pro-inflammatory M1-like phenotype by ceRNA effect of miR-136-5p and lncRNA HOTAIR in cuprizone-induced demyelination. Our findings show the therapeutic potential of SF for human MS probably by targeting epigenetic regulation in microglia.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Duan C,Liu Y,Li Y,Chen H,Liu X,Chen X,Yue J,Zhou X,Yang J

doi

10.1016/j.bcp.2018.06.028

subject

Has Abstract

pub_date

2018-09-01 00:00:00

pages

110-123

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(18)30243-0

journal_volume

155

pub_type

杂志文章

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Sulfasalazine alters microglia phenotype by competing endogenous RNA effect of miR-136-5p and long non-coding RNA HOTAIR in cuprizone-induced demyelination.