MicroRNA-21 silencing prolongs islet allograft survival by inhibiting Th17 cells.

It has been reported that microRNA-21 (miR-21) augments Th17 responses and contributes to the pathogenesis of autoimmune diseases. Gene knockout or siRNA-induced knockdown of miR-21 in mice resulted in impaired Th17 differentiation and strong resistance to experimental autoimmune encephalomyelitis (EAE). Recently, we validated the miR-21 target IL-10 mRNA and showed that it exerts a pro-inflammatory role by inhibiting IL-10-expressing regulatory B cell (B10) differentiation. The administration of miR-21 antisense oligonucleotides (antagomiR-21) in vivo potently suppressed the severity of EAE, and the suppressive activity was mediated by an increased number of B10 cells. However, the contribution of the miR-21 pathways involved in transplant rejection remains obscure. In this study, we examined the impact of systemic administration of miR-21 inhibitor on allografts in a pancreatic islet transplantation model. We showed that specific miR-21 silencing in vivo significantly prolonged allograft survival (median survival time (MST) 21 days with antagomiR-21 vs 13 days for the control, p < 0.05), and the change was associated with a decrease in Th17 cells (~3-fold) and an increase in B10 cells (~2.4-fold). Moreover, we found that miR-21-silenced B cells mediate this protective role through pro-inflammatory Th17 responses in an IL-10-dependent fashion. Thus, we have revealed a novel mechanistic pathway that modulates Th17 development and alloimmunity. Targeting miR-21 may represent a valuable therapeutic intervention strategy for preventing transplant rejection.