Elsevier

Journal of Autoimmunity

Volume 89, May 2018, Pages 41-52
Journal of Autoimmunity

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

https://doi.org/10.1016/j.jaut.2017.11.005Get rights and content
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Highlights

  • Th1 cells expressing miR-148a mediate colitis in a murine model of IBD.

  • Antagomir-148a inhibits colitis by selectively depleting Th1 cells from the colon.

  • Antagomir-148a does not affect the protective immunological memory.

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

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

Cited by (0)

1

Present address: Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie & Medizin Inselspital, University of Bern, Bern, Switzerland.

2

Present address: Max Planck Institute for Evolutionary Biology, Evolutionary Genomics Group, Plön, Germany.

3

A.R. and M.F.M. equal contribution.