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 miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 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 miR-351 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 miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre–miR-351. Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.
Adeno-Associated Virus Serotype 2 Vector–Mediated Reintroduction of microRNA-19b Attenuates Hepatic Fibrosis
