title: miR-155-3p Drives the Development of Autoimmune Demyelination by Regulation of Heat Shock Protein 40.
abstract: microRNA-155 (miR-155) plays an important role in posttranscriptional gene regulation of the immune system. We and others have described miR-155 upregulation in T helper cells (Th) during the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We have shown that mice in which the miR-155 host gene (MIR155HG) has been deactivated are resistant to EAE. MIR155HG produces two different miRNA strands, miR-155-5p and miR-155-3p, and miR-155-5p has been considered the only functional miR-155 form. Surprisingly, we found that miR-155-3p is also strongly upregulated in Th cells infiltrating the brain in EAE. Functional manipulation of miR-155-3p expression revealed its particular role in regulation of Th17 development. The search for miRNA-155-3p target genes highlighted transcripts of two heat shock protein 40 genes, Dnaja2 and Dnajb1. These two genes negatively regulated Th17 differentiation, leading to decreased EAE. Therefore, our findings provide new insights into a previously unknown mechanism by which miR-155-3p controls Th17 cell differentiation and autoimmune demyelination.
  
  
  CONCLUSIONS
  Multiple sclerosis (MS) is brain-specific autoimmune disease mediated by T helper (Th) cells autoreactive to myelin. The mechanisms leading to MS are not fully understood and microRNAs (miRNAs) emerge as important regulators of the process. We report that, in an MS murine model of experimental autoimmune encephalomyelitis, miR-155 controls Th cell function by an unusual mechanism involving a rare form, miR-155-3p. miR-155-3p is specifically found in brain-infiltrating myelin-autoreactive CD4(+) T cells and contributes to the development of an encephalitogenic Th17 population. miR-155-3p promotes Th17 by inhibiting two heat shock protein 40 genes, Dnaja2 and Dnajb1. Our findings indicate a unique miRNA function in the brain-infiltrating Th cells and suggest Dnaja2 and Dnajb1 as targets for intervention in autoimmune demyelination.
authors.affiliation: Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, 90-153 Lodz, Poland.
authors.forename: Marcin P
authors.initials: MP
authors.lastname: Mycko
authors.affiliation: Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, 90-153 Lodz, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Cichalewska
authors.affiliation: Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, 90-153 Lodz, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cwiklinska
authors.affiliation: Department of Neurology, Laboratory of Neuroimmunology, Medical University of Lodz, 90-153 Lodz, Poland kselmaj@afazja.am.lodz.pl.
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Selmaj
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000235:genetics* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D009103:Multiple Sclerosis / Q000235:genetics / Q000473:pathology; D058504:Th17 Cells
chemical_list: D004268:DNA-Binding Proteins; C494641:Dnajb1 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C499308:Rag2 protein, mouse
keywords: T helper cells; autoimmune demyelination; experimental autoimmune encephalomyelitis; heat shock proteins; microRNA; multiple sclerosis