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 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. Conclusion 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.

Antischistosomiasis Liver Fibrosis Effects of Chlorogenic Acid through IL-13/miR-21/Smad7 Signaling Interactions In Vivo and In Vitro

“…Researchers have found that the IL-13/miR-21/Smad7 signaling interactions in hepatic stellate cells are equally important in the two signaling pathways that can influence the formation of collagen and play an important role in the development of schistosome-induced hepatic fibrosis (27). The receptors (IL-13R␣1/IL-4R␣) on hepatic stellate cells were stimulated by IL-13 through Smad1/2 (Smad1/5 and Smad2/3) phosphorylation (7), positively regulating production of miR-21 and then interfering with the target genes of miR-21 and Smad7 and subsequently preventing Smad7 from negative-feedback regulation of Smad1/2 (Smad1/5 and Smad2/3).…”

MicroR-146 blocks the activation of M1 macrophage by targeting signal transducer and activator of transcription 1 in hepatic schistosomiasis

“…Numerous studies have demonstrated that miRNAs play a crucial role in many human diseases including schistosomiasis (He et al, 2013, He et al, 2015, Cai et al, 2013, Cai et al, 2016, Han et al, 2013). Our previous study using miRNA microarrays demonstrated that a series of miRNAs were deregulated in the progression of hepatic schistosomiasis in a mouse model.…”

“…Our previous study using miRNA microarrays demonstrated that a series of miRNAs were deregulated in the progression of hepatic schistosomiasis in a mouse model. Importantly, miR-21, one of the upregulated miRNAs, was involved in the regulation of activation of hepatic stellate cells (HSCs) and downregulation of miR-21 prevented lethal infection by repressing both TGF-β1 and IL-13 pathways (He et al, 2015). …”

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

“…Recently, miR-21 has been ascribed a crucial role in the regulation of cellular activity during physiological and pathological processes [31]. miR‑21 is widely expressed and has been found to be increased in organs and tissues which have suffered fibrogenesis or remodeling, including the heart [32], kidney [33], lung [34], asthmatic airways [35, 36], liver [37, 38], skin [39-41], and tumor tissue [42, 43]. Studies revealed that enhanced miR-21 expression is involved in the progression of lung fibrosis, and TGF-β1 plays an important role in mediating increased miR-21 expression [34, 44].…”