Recombinant adeno-associated virus-mediated inhibition of microRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and transforming growth factor beta 1 pathways
Gene Therapy Center; Department of Microbiology and Physiological Systems
Adenoviridae; Animals; Down-Regulation; Hepatic Stellate Cells; Interleukin-13; Liver Diseases, Parasitic; Male; Mice, Inbred BALB C; MicroRNAs; Schistosomiasis; Smad7 Protein; Transforming Growth Factor beta1
Cellular and Molecular Physiology | Digestive System Diseases | Genetics and Genomics | Hepatology | Parasitic Diseases | Therapeutics | Translational Medical Research
Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs (miRNAs) could mitigate disease outcomes. Here, we showed that progressive hepatic schistosomiasis caused elevation of miR-21 and efficient and sustained inhibition of miR-21 by using highly hepatic tropic adeno-associated virus serotype 8 (rAAV8), which protected mice against lethal schistosome infection through attenuation of hepatic fibrosis (HF). We demonstrated an additive role of interleukin (IL)-13 and transforming growth factor beta 1 (TGF-beta1) in up-regulating miR-21 expression in hepatic stellate cells (HSCs) by activation of mothers against decapentaplegic (SMAD) proteins. Furthermore, down-regulation of miR-21 in HSCs reversed HF by enhancing SMAD7 expression, thus repressing TGF-beta1/Smad and IL-13/Smad pathways. CONCLUSION: This study suggests the mechanism of IL-13-mediated schistosomiasis HF by up-regulation of miR-21 and highlights the potential of rAAV8-mediated miR-21 inhibition as a therapeutic intervention for hepatic fibrotic diseases, such as schistosomiasis.
DOI of Published Version
Hepatology. 2015 Jun;61(6):2008-17. doi: 10.1002/hep.27671. Epub 2015 Apr 15. Link to article on publisher's site
Hepatology (Baltimore, Md.)
He, Xing; Xie, Jun; Zhang, Dongmei; Su, Qin; Sai, Xue; Bai, Ruipu; Chen, Chao; Luo, Xufeng; Gao, Guangping; and Pan, Weiqing, "Recombinant adeno-associated virus-mediated inhibition of microRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and transforming growth factor beta 1 pathways" (2015). UMass Center for Clinical and Translational Science Supported Publications. 43.