Xing He1, Jun Xie2,3, Dongmei Zhang1, Qin Su2, Xue Sai1, Ruipu Bai1, Chao Chen1, Xufeng Luo1, Guangping Gao2,3, Weiqing Pan1. 1. Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China. 2. Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 3. Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Abstract
UNLABELLED: 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. 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.
UNLABELLED: 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. 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.
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