rAAV8-mediated inhibition of miRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and TGF-β1 pathways
Identifieur interne : 000368 ( Main/Merge ); précédent : 000367; suivant : 000369rAAV8-mediated inhibition of miRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and TGF-β1 pathways
Auteurs : Xing He [République populaire de Chine] ; Jun Xie [États-Unis] ; Dongmei Zhang [République populaire de Chine] ; Qin Su [États-Unis] ; Xue Sai [République populaire de Chine] ; Ruipu Bai [République populaire de Chine] ; Chao Chen [République populaire de Chine] ; Xufeng Luo [République populaire de Chine] ; Guangping Gao [États-Unis] ; Weiqing Pan [République populaire de Chine]Source :
- Hepatology (Baltimore, Md.) [ 0270-9139 ] ; 2015.
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 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) protected mice against the lethal schistosome infection through the attenuation of hepatic fibrosis. We demonstrated an additive role of IL-13 and TGF-β1 in up-regulating the miR-21 expression in the hepatic stellate cells (HSCs) by activation of the SMAD proteins. Further, the down-regulation of miR-21 in the HSCs reversed hepatic fibrosis by enhancing SMAD7 expression, thus repressing TGF-β1/Smad and IL-13/Smad pathways.
Our study revealed the mechanism of IL-13-mediated schistosomiasis hepatic fibrosis 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.
Url:
DOI: 10.1002/hep.27671
PubMed: 25546547
PubMed Central: 4441614
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<front><div type="abstract" xml:lang="en"><p id="P2">Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs 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) protected mice against the lethal schistosome infection through the attenuation of hepatic fibrosis. We demonstrated an additive role of IL-13 and TGF-β1 in up-regulating the miR-21 expression in the hepatic stellate cells (HSCs) by activation of the SMAD proteins. Further, the down-regulation of miR-21 in the HSCs reversed hepatic fibrosis by enhancing SMAD7 expression, thus repressing TGF-β1/Smad and IL-13/Smad pathways.</p>
<sec id="S1"><title>Conclusion</title>
<p id="P3">Our study revealed the mechanism of IL-13-mediated schistosomiasis hepatic fibrosis 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.</p>
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