1. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo.
- Author
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Maschmeyer P, Petkau G, Siracusa F, Zimmermann J, Zügel F, Kühl AA, Lehmann K, Schimmelpfennig S, Weber M, Haftmann C, Riedel R, Bardua M, Heinz GA, Tran CL, Hoyer BF, Hiepe F, Herzog S, Wittmann J, Rajewsky N, Melchers FG, Chang HD, Radbruch A, and Mashreghi MF
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Humans, Mice, Mice, Inbred C57BL, Nuclear Proteins genetics, Nuclear Proteins metabolism, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, Twist-Related Protein 1 genetics, Twist-Related Protein 1 metabolism, Antagomirs genetics, Colitis immunology, Colon immunology, Inflammation immunology, MicroRNAs genetics, Th1 Cells physiology
- 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., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
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