Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo
Authors
- P. Maschmeyer
- G. Petkau
- F. Siracusa
- J. Zimmermann
- F. Zügel
- A.A. Kühl
- K. Lehmann
- S. Schimmelpfennig
- M. Weber
- C. Haftmann
- R. Riedel
- M. Bardua
- G.A. Heinz
- C.L. Tran
- B.F. Hoyer
- F. Hiepe
- S. Herzog
- J. Wittmann
- N. Rajewsky
- F.G. Melchers
- H.D. Chang
- A. Radbruch
- M.F. Mashreghi
Journal
- Journal of Autoimmunity
Citation
- J Autoimmun 89: 41-52
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.