Abstract
Alcohol abuse can induce brain injury and neurodegeneration, and recent evidence shows the participation of immune receptors toll-like in the neuroinflammation and brain damage. We evaluated the role of miRNAs as potential modulators of the neuroinflammation associated with alcohol abuse and the influence of the TLR4 response. Using mice cerebral cortex and next-generation sequencing (NGS), we identified miRNAs that were differentially expressed in the chronic alcohol-treated versus untreated WT or TLR4-KO mice. We observed a differentially expression of miR-183 Cluster (C) (miR-96/-182/-183), miR-200a and miR-200b, which were down-regulated, while mirR-125b was up-regulated in alcohol-treated WT versus (vs.) untreated mice. These miRNAs modulate targets genes related to the voltage-gated sodium channel, neuron hyperexcitability (Nav1.3, Trpv1, Smad3 and PP1-γ), as well as genes associated with innate immune TLR4 signaling response (Il1r1, Mapk14, Sirt1, Lrp6 and Bdnf). Functional enrichment of the miR-183C and miR-200a/b family target genes, revealed neuroinflammatory pathways networks involved in TLR4 signaling and alcohol abuse. The changes in the neuroinflammatory targets genes associated with alcohol abuse were mostly abolished in the TLR4-KO mice. Our results show the relationship between alcohol intake and miRNAs expression and open up new therapeutically targets to prevent deleterious effects of alcohol on the brain.
Highlights
MicroRNAs are a family of small non-coding RNA that derives from endogenous long transcripts, whose function as regulators of gene expression through translational repression has been demonstrated[1,2]
By conducting next-generation sequencing (NGS) along with bioinformatics to identify the miRNAs affected by chronic alcohol consumption and the role of TLR4 response in the mouse cerebral cortex, we identified some miRNAs that were differently expressed in the cortices of the chronic alcohol-treated mice, targeted neuronal excitability, TLR4 signaling response and inflammation
Several studies have demonstrated that alcohol abuse deregulated miRNAs, and changes in miRNAs have been identified in post-mortem frontal cortices and other regions of human alcoholics[18,65], and even in the cortices of alcohol-dependent mice[17,66,67,68]
Summary
MicroRNAs (miRNAs) are a family of small non-coding RNA (about 21–25 nucleotides) that derives from endogenous long transcripts (pri-miRNAs), whose function as regulators of gene expression through translational repression has been demonstrated[1,2]. Our previous findings indicate the critical role of the TLR4 response in the neuroinflammatory response induced by alcohol and its contribution to brain damage and behavioral dysfunctions associated with alcohol abuse[14,21]. By considering the influence of miRNAs as regulators of immune system, the aim of the present study is to explore the modulatory role of the miRNAs induced by chronic alcohol intake through the TLR4 response in the brain. To this end, we used cortices of WT and TLR4-KO with and without chronic alcohol treatment and the next-generation sequencing (high-throughput sequencing) technique to identify the miRNA profiles that could be differentially expressed. The results will provide a new direction for future applications of miRNAs alcohol diagnosis and treatment
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