miR26a Modulates T_h17/T_reg Balance in the EAE Model of Multiple Sclerosis by Targeting IL6

A number of different microRNAs (miRNAs) have been implicated in various autoimmune diseases, including multiple sclerosis (MS). T helper (T_h)17 and regulatory T cells (T_regs) have likewise been implicated as key players in MS, and a functional imbalance of these cell types is increasingly recognized as a key etiological factor in the disease. Although specific panels of transcription factors and cytokines are known to regulate the T_h17/T_reg balance, the role of noncoding RNAs remains poorly understood. The inflammatory cytokine, interleukin (IL)6, appears to play a critical role in both the development of the T_h17 response and the inhibition of T_reg functions. In this research, an IL6-associated miRNA, miR26a, was identified, and its normally downregulated expression was shown to be highly correlated with disease severity in patients suffering from MS as well as in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE; a well-established animal model of human MS). Using the EAE model system, in vivo silencing of miR26a was found to result in increased expression of T_h17-related cytokines and increased severity of EAE, while overexpression of miR26a was found to result in reduced expression of T_h17-related cytokines and a milder form of EAE. By contrast, T_reg cell-specific transcription factor, Foxp3, was found to be positively correlated with miR26a expression. Finally, miR26a was found to downregulate T_h17 and to upregulate T_reg cell function through its targeting of IL6. Taken together, our data indicate an important role for miR26a in maintaining the T_h17 and T_reg cell balance in MS that involves repression of IL6 expression.