title: Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats.
abstract: MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Bergman
authors.forename: Tojo
authors.initials: T
authors.lastname: James
authors.forename: Lara
authors.initials: L
authors.lastname: Kular
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ruhrmann
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kramarova
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.forename: Gordana
authors.initials: G
authors.lastname: Supic
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.forename: Andor
authors.initials: A
authors.lastname: Pivarcsi
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011919:Rats, Inbred Strains; D017423:Sequence Analysis, RNA / Q000379:methods / Q000639:trends; D013045:Species Specificity
chemical_list: D035683:MicroRNAs