JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation

Abstract

Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (-SMA) and of collagen assessed by quantitative PCR and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1-treated Schistosoma-infected mice for RNA-sequencing analysis. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in HSC transdifferentiation into myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg-induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum. Author summaryWhen a host is infected with Schistosoma, a common parasite that affects more than a million people and hundreds of thousands of livestock, the parasite deposits eggs in the liver of the host. The eggs lead to liver inflammation, which activates stellate cells in the liver. These stellate cells generate most of the excessive extracellular matrix that replaces healthy liver parenchyma with fibrous tissue, causing liver fibrosis. Schistosoma japonicum causes the most severe liver damage of all the schistosome parasites. Therefore, inhibiting the activation of the liver stellate cells and removing the activated stellate cells are key strategies for treating liver fibrosis caused by this parasite. JQ-1 is a potent inhibitor of the BET family of bromodomain proteins and is structurally similar to inhibitors being tested in clinical trials for various types of cancers. Here we found that administering JQ-1 to mice infected with S. japonicum decreased the degree of liver fibrosis. JQ-1 inhibited the activation and proliferation of liver stellate cells by blocking the phosphorylation and thus the activation of JAK2 and STAT3 to achieve its therapeutic effects. Thus, this study provides insights into the development of new therapeutic strategies for Schistosoma-induced liver fibrosis.