MicroRNA-448 Promotes Multiple Sclerosis Development Through Induction of Th17 Response Through Targeting Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2)

Biochem Biophys Res Commun. 2017 May 6;486(3):759-766. doi: 10.1016/j.bbrc.2017.03.115. Epub 2017 Mar 23.

Abstract

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system, and its pathogenesis remains largely unclear. Much attention has been paid to the role of microRNAs (miRs) in regulation of autoimmune disease. Here, we found, for the first time, that miR-448 expression was significantly increased in periphery blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) of patients with MS, and its expression positively correlated with the disease severity. We further demonstrated that CD4+ T cells, especially the Th17 lineage, were the major source of miR-448 expression. Using gain- and loss-of-function approaches, we further verified that miR-448 could enhance Th17 differentiation, characterized by up-regulated expression levels of IL-17A and RORγt. Interleukin (IL)-1β as a potent driver of pathogenic Th17 cells was able to strongly induce miR-448 expression in CD4+ T cells through activating NF-κB pathway. Additionally, we identified that miR-448 directly targeted protein tyrosine phosphatase non-receptor type 2 (PTPN2), which has been known as an anti-inflammatory player with capacity to suppress Th17 differentiation. We also observed markedly decreased expression of PTPN2 in PBMC and CSF of MS patients. Our results suggest that miR-448 might promote Th17 differentiation in MS and thus aggravate the disease through inhibiting PTPN2.

Keywords: IL-1β; Multiple sclerosis; PTPN2; Th17; miR-448.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Case-Control Studies
  • Cell Differentiation
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Interleukin-17 / genetics*
  • Interleukin-17 / immunology
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Luciferases / genetics
  • Luciferases / metabolism
  • MicroRNAs / genetics*
  • MicroRNAs / immunology
  • Multiple Sclerosis / diagnosis
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • Neutrophils / immunology
  • Neutrophils / pathology
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
  • Primary Cell Culture
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / immunology
  • Remission Induction
  • Severity of Illness Index
  • Signal Transduction
  • Th17 Cells / immunology
  • Th17 Cells / pathology*

Substances

  • IL1B protein, human
  • Interleukin-17
  • Interleukin-1beta
  • MIRN448 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Luciferases
  • PTPN2 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2