MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis

• Published in: The Journal of clinical investigation Vol. 125; no. 3; pp. 1069 - 1080
• Main Authors: Murugaiyan, Gopal, da Cunha, Andre Pires, Ajay, Amrendra K, Joller, Nicole, Garo, Lucien P, Kumaradevan, Sowmiya, Yosef, Nir, Vaidya, Vishal S, Weiner, Howard L
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2015
• Subjects: Animals; Autoimmune diseases; Base Sequence; Binding Sites; Biomedical research; Care and treatment; Cell Differentiation; Cells, Cultured; Encephalomyelitis; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Gene Expression; Hospitals; Immune system; Interleukin-17 - genetics; Interleukin-17 - metabolism; Lymphocytes; Mice, Inbred C57BL; MicroRNA; MicroRNAs - physiology; Physiological aspects; Rheumatology; RNA Interference; Smad7 Protein - genetics; Smad7 Protein - metabolism; Studies; Th17 Cells - physiology; Transcription factors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci74347

Accumulation of IL-17-producing Th17 cells is associated with the development of multiple autoimmune diseases; however, the contribution of microRNA (miRNA) pathways to the intrinsic control of Th17 development remains unclear. Here, we demonstrated that miR-21 expression is elevated in Th17 cells and that mice lacking miR-21 have a defect in Th17 differentiation and are resistant to experimental autoimmune encephalomyelitis (EAE). Furthermore, we determined that miR-21 promotes Th17 differentiation by targeting and depleting SMAD-7, a negative regulator of TGF-β signaling. Moreover, the decreases in Th17 differentiation in miR-21-deficient T cells were associated with defects in SMAD-2/3 activation and IL-2 suppression. Finally, we found that treatment of WT mice with an anti-miR-21 oligonucleotide reduced the clinical severity of EAE, which was associated with a decrease in Th17 cells. Thus, we have characterized a T cell-intrinsic miRNA pathway that enhances TGF-β signaling, limits the autocrine inhibitory effects of IL-2, and thereby promotes Th17 differentiation and autoimmunity.