Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response

Abstract

Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disorder characterized by recurrent seizures. The pathogenic mechanisms underlying mTLE may involve defects in the post-transcriptional regulation of gene expression. MicroRNAs (miRNAs) are non-coding RNAs that control the expression of genes at the post-transcriptional level. Here, we performed a genome-wide miRNA profiling study to examine whether miRNA-mediated mechanisms are affected in human mTLE. miRNA profiles of the hippocampus of autopsy control patients and two mTLE patient groups were compared. This revealed segregated miRNA signatures for the three different patient groups and 165 miRNAs with up- or down-regulated expression in mTLE. miRNA in situ hybridization detected cell type-specific changes in miRNA expression and an abnormal nuclear localization of select miRNAs in neurons and glial cells of mTLE patients. Of several cellular processes implicated in mTLE, the immune response was most prominently targeted by deregulated miRNAs. Enhanced expression of inflammatory mediators was paralleled by a reduction in miRNAs that were found to target the 3′-untranslated regions of these genes in reporter assays. miR-221 and miR-222 were shown to regulate endogenous ICAM1 expression and were selectively co-expressed with ICAM1 in astrocytes in mTLE patients. Our findings suggest that miRNA changes in mTLE affect the expression of immunomodulatory proteins thereby further facilitating the immune response. This mechanism may have broad implications given the central role of astrocytes and the immune system in human neurological disease. Overall, this work extends the current concepts of human mTLE pathogenesis to the level of miRNA-mediated gene regulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-0992-7) contains supplementary material, which is available to authorized users.

microRNA s (9, 138, 181A, 221, and 222) and mesial temporal lobe epilepsy in developing brains

“…MiR-34a is upregulated and contributed in seizure-induced neuronal death [28]. Kan et al (2012) profiled the miRNAs changes in human TLE [17]. Our previous experiments supported the role of inflammation-related miRNAs (miR-146a, -155, -21, and -132) and brain-specific miRNAs (miR-124 and -134) in the pathogenesis of MTLE in immature rat models and children [20,29,30].…”

“…In vitro experiments have revealed that miR-221 and miR-222 target the 3´UTR of intercellular adhesion molecule 1 (ICAM1) [17], which in turn mediates interactions with immune cells to influence the inflammatory process [18].…”

Neuroprotection of microRNA in neurological disorders (Review)

“…Furthermore, deregulated miRNAs are prominently targeted by immune proteins. For example, miR-221 and miR-222 are found to regulate intercellular adhesion molecule 1 (ICAM1) expression and are co-expressed with ICAM1 in astrocytes in MTLE patients (66). Aberrant miRNA in MTLE has been suggested to affect the expression of immunomodulatory proteins, by facilitating the immune response.…”

Epigenetics and Epilepsy

“…DNMTs are also direct targets of miRNAs, in particular the miR-29 family (Fabbri et al 2007), which are also regulated in epilepsy (Hu et al 2011b;Risbud and Porter 2013). Among miRNAs for which direct effects have been identified on transcription, let-7 family members, although not miR-320, have been found to be changed in a number of models/human epileptic tissue (Kan et al 2012;McKiernan et al 2012b;Risbud and Porter 2013). Also, loss of miR-101 was reported to result in increased expression of a histone-modifying enzyme (Varambally et al 2008).…”