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

• DOI: 10.1016/j.jaut.2017.11.005
• Publication Date: 2017-12-02T03:02:29Z
• Authors: Patrick Maschmeyer; Georg Petkau; Francesco Siracusa; Jakob Zimmermann; Franziska Zügel; Anja Andrea Kühl; Katrin Lehmann; Sarah Schimmelpfe...; Melanie Weber; Claudia Haftmann; René Riedel; Markus Bardua; Gitta Anne Heinz; Cam Loan Tran; Bimba Franziska H...; Falk Hiepe; Sebastian Herzog; Jürgen Wittmann; Nikolaus Rajewsky; Fritz Georg Melchers; Hyun-Dong Chang; Andreas Radbruch; Mir-Farzin Mashreghi
• Keywords: Oligonucleotide therapy; Colon; Article; Inflammatory bowel disease; Mice; 03 medical and health sciences; Animals; Humans; T-bet Transcription Factor; Cells, Cultured; Inflammation; 0303 health sciences; Twist-Related Protein 1; Antagomirs; Pro-inflammatory Th1 cells; Nuclear Proteins; Cell Differentiation; Chronic inflammation; Th1 Cells; Colitis; miRNA-148a; Mice, Inbred C57BL; Disease Models, Animal; MicroRNAs; T-Box Domain Proteins; Pre-clinical study

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.