MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis
Gopal Murugaiyan, … , Vishal S. Vaidya, Howard L. Weiner
Gopal Murugaiyan, … , Vishal S. Vaidya, Howard L. Weiner
Published March 2, 2015; First published February 2, 2015
Citation Information: J Clin Invest. 2015;125(3):1069-1080. https://doi.org/10.1172/JCI74347.
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Research Article Immunology

MicroRNA-21 promotes Th17 differentiation and mediates experimental autoimmune encephalomyelitis

Abstract

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.

Authors

Gopal Murugaiyan, Andre Pires da Cunha, Amrendra K. Ajay, Nicole Joller, Lucien P. Garo, Sowmiya Kumaradevan, Nir Yosef, Vishal S. Vaidya, Howard L. Weiner

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Figure 1

miR-21 is specifically induced in Th17 cells.

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miR-21 is specifically induced in Th17 cells. (A and B) Naive CD4+CD62Lh...
(A and B) Naive CD4+CD62LhiCD44lo T cells were activated with plate-bound anti-CD3 (2 μg/ml) and anti-CD28 (2 μg/ml) in the presence of Th1-, Th2-, Th17-, and Treg-polarizing conditions in vitro. Twenty-four hours later, miR-21 expression was analyzed by quantitative RT-PCR (qRT-PCR) using the snRNAs snoRNA135 and U6 snRNA as endogenous controls. (C) qRT-PCR analysis of miR-21 expression in flow cytometric–sorted CCR6+CD4+ and CCR6–CD4+ T cells from in vitro Th17 cultures. (D) CD4+ T cells from C57BL/6 mice were sorted into IL-17A+ and IL-17A– cell populations and analyzed for expression of miR-21 by qRT-PCR. Data are representative of 3 independent experiments. Error bars represent the mean ± SEM. **P < 0.01 and ***P < 0.001 by unpaired Student’s t test. Med, medium.