AUTHOR=Chen Yang , Hu Yuan , Zhou Hao , Jiang Nan , Wang Yiluo , Zhang Jing , Shen Yujuan , Yu Guoying , Cao Jianping 

TITLE=Induction of hepatic fibrosis in mice with schistosomiasis by extracellular microRNA-30 derived from Schistosoma japonicum eggs

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1425384

DOI=10.3389/fimmu.2024.1425384

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host’s immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by <italic>S. japonicum</italic> contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of <italic>S. japonicum</italic> secrete miRNA-30, a novel miRNA.</p></sec><sec><title>Methods</title><p><italic>In vitro</italic>, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges.</p></sec><sec><title>Results</title><p>This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, <italic>in vitro</italic>, i.e., it significantly increases the fibrogenic factors <italic>Col1</italic>(<italic>α1</italic>), <italic>Col3</italic>(<italic>α1</italic>), and <italic>α-SMA</italic> at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, <italic>in vivo</italic> experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of <italic>Col1</italic>(<italic>α1</italic>), <italic>Col3</italic>(<italic>α1</italic>), and <italic>α</italic>-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the <italic>in vivo</italic> silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, <italic>in vivo</italic>, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with <italic>S. japonica</italic>.</p></sec><sec><title>Conclusions</title><p>The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.</p></sec>