<i>MicroRNA-351</i> promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor

Abstract

Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host <i>miR-351</i> in HSCs was markedly reduced during the early stage of <i>Schistosoma</i> infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of <i>miR-351</i> promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of <i>miR-351</i> in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that <i>miR-351</i> is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of <i>miR-351</i> in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of <i>pre-miR-351</i> Our study provides insights into the mechanisms by which <i>miR-351</i> regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated <i>miR-351</i> inhibition as a therapeutic intervention for fibrotic diseases.