title: 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.
abstract: 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-β1) 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-β1/Smad and IL-13/Smad pathways.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Xing
authors.initials: X
authors.lastname: He
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Sai
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Ruipu
authors.initials: R
authors.lastname: Bai
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Luo
authors.affiliation: Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.
authors.forename: Weiqing
authors.initials: W
authors.lastname: Pan
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism*; D008109:Liver Diseases, Parasitic / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D012552:Schistosomiasis / Q000209:etiology* / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D018793:Interleukin-13; D035683:MicroRNAs; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; C497807:Smad7 protein, mouse; C508961:Tgfb1 protein, mouse; C531950:MIRN21 microRNA, mouse