title: 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.
authors.affiliation: Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
authors.forename: Anne A
authors.initials: AA
authors.lastname: Kan
authors.forename: Susan
authors.initials: S
authors.lastname: van Erp
authors.forename: Alwin A H A
authors.initials: AA
authors.lastname: Derijck
authors.forename: Marina
authors.initials: M
authors.lastname: de Wit
authors.forename: Ellen V S
authors.initials: EV
authors.lastname: Hessel
authors.forename: Eoghan
authors.initials: E
authors.lastname: O'Duibhir
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Peter C
authors.initials: PC
authors.lastname: Van Rijen
authors.forename: Peter H
authors.initials: PH
authors.lastname: Gosselaar
authors.forename: Pierre N E
authors.initials: PN
authors.lastname: de Graan
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000473:pathology; D001483:Base Sequence; D016022:Case-Control Studies; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D015894:Genome, Human; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D008297:Male; D035683:MicroRNAs; D008875:Middle Aged; D008969:Molecular Sequence Data; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D035683:MicroRNAs; C525709:MIR221, human; C525710:MIR222, human