Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo

J Autoimmun. 2018 May;89:41-52. doi: 10.1016/j.jaut.2017.11.005. Epub 2017 Dec 1.

Abstract

In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.

Keywords: Antagomirs; Chronic inflammation; Inflammatory bowel disease; Oligonucleotide therapy; Pre-clinical study; Pro-inflammatory Th1 cells; miRNA-148a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antagomirs / genetics*
  • Cell Differentiation
  • Cells, Cultured
  • Colitis / immunology*
  • Colon / immunology*
  • Disease Models, Animal
  • Humans
  • Inflammation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Th1 Cells / physiology*
  • Twist-Related Protein 1 / genetics
  • Twist-Related Protein 1 / metabolism

Substances

  • Antagomirs
  • MicroRNAs
  • Mirn148 microRNA, mouse
  • Nuclear Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • antagomir-148a