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.

Traumatic brain injury increases levels of miR‐21 in extracellular vesicles: implications for neuroinflammation

“…However, the identification of changes in miR‐21 expression in EVs after TBI agrees with increases in whole brain tissue observed by others . Other than TBI, increased expression of miR‐21 has also been observed in many models of neuroinflammation and neuronal injury .…”

ERK phosphorylation and miR-181a expression modulate activation of human memory TH17 cells

“…Such reduced threshold of activation of T H 17 cells compared with other T-cell subsets may lead to increased responses to a specific antigen. Of note, miR-181a was recently associated with the susceptibility to develop EAE in rats, showing higher expression in a strain susceptible to EAE compared with an EAE-resistant one 42 , pointing towards a potential role for miR-181a in regulating specific T H 17-cell responses in autoimmunity.…”

Role of miR-181a in the process of apoptosis of multiple malignant tumors: A literature review

“…Bergman et al have demonstrated that the PRKCD gene is a direct target of miR-181a in a rat model of multiple sclerosis. 47 Ke et al and Chen et al found that miR-181a could inhibit the irradiation-and cisplatininduced apoptosis of human squamous cervical carcinoma cells via downregulating the expression levels of PRKCD. 48,49 PBX3 PBX3, a HOXA cofactor gene, can encode pre-B-cell leukemia transcription factor 3, which is capable of regulating the transcription of downstream targets by forming stable heterocomplexes with HOX and MEIS proteins.…”