MicroRNA-351 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 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.

• Authors: Xing He, Yue Sun, Nanhang Lei, Xiaobin Fan, Cheng Zhang, Yange Wang, Kuiyang Zheng, Dongmei Zhang, Weiqing Pan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 1 Pg. 180-185 (01 02 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29255036 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IFNG protein, mouse
• MIRN351 microRNA, 351
• MicroRNAs
• Receptors, Calcitriol
• Interferon-gamma

Topics

• Animals
• Hepatic Stellate Cells (immunology, pathology)
• Interferon-gamma (immunology)
• Liver (immunology, parasitology, pathology)
• Liver Cirrhosis (immunology, pathology, therapy)
• Male
• Mice
• Mice, Inbred BALB C
• MicroRNAs (immunology)
• Receptors, Calcitriol (immunology)
• Schistosoma (immunology)
• Schistosomiasis (immunology, pathology, therapy)