Enhanced Wnt Signalling in Hepatocytes is Associated with Schistosoma japonicum Infection and Contributes to Liver Fibrosis

Abstract

Liver fibrosis is the most serious pathology caused by Schistosoma japonicum infection, which arises when schistosome eggs are deposited in the liver. Eosinophils, macrophages and hepatic stellate cells (HSCs) have been identified as major cellular contributors to the development of granulomas and fibrosis, but little is known about the effects of hepatocytes on granuloma formation. Here, we found that the levels of Wnt signalling-related molecules, transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF) in hepatocytes were markedly elevated after S. japonicum infection. Liver fibrosis was exacerbated when exogenous Wnt3a was introduced, but was alleviated when Wnt signalling was suppressed by DKK1, accompanied by the reduced expression of TGF-β and CTGF in hepatocytes. These results indicate that the hepatocytic expression of TGF-β and CTGF is mediated by Wnt signalling. Additionally, the hepatocytes isolated from infected mice promoted the activation of primary HSCs in vitro, however, this effect was not observed when hepatocytes from DKK1 treated S. japonicum-infected mice was employed in the co-culture system. Our findings identify a novel pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis that is dependent on Wnt signalling, which may serve as a potential target for ameliorating hepatic fibrosis caused by helminths.

Study of Dickkopf-1 (DKK-1) in patients with chronic viral hepatitis C-related liver cirrhosis with and without hepatocellular carcinoma

“…The healthy control group was selected as nonfibrotic patients as the pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis is dependent on the Wnt signaling pathway [21]. Figure 1 shows the level of serum DKK-1 in the studied groups, where there was a difference in the median serum level in the present study control group and other studies' healthy control group (115 pg/ml and 1201.46 pg/ml respectively) [22,23].…”

Myricetin Possesses Anthelmintic Activity and Attenuates Hepatic Fibrosis via Modulating TGFβ1 and Akt Signaling and Shifting Th1/Th2 Balance in Schistosoma japonicum-Infected Mice

“…As the infection enters the chronic phase, the egg granuloma size becomes smaller, and Treg cells are activated, and Th1/Th2 immune balance is regulated and maintained, thereby inhibiting the development of liver fibrotic lesions (42,43). Additionally, Th17 cells are positively correlated with liver pathological damage, and the use of IL-17 neutralizing antibodies can effectively lessen egg granulomatous lesions (44). By detecting CD4 + T cell subtypes from spleen cells of mice infected with S. japonicum after 7 weeks of infection, we found that myricetin increased the proportion of Th1 cells but decreased the proportion of Th2 and Th17 cells, and ELISA also demonstrated elevations in plasma IFN-γ, IL-12, and IL-7 with concurrent reductions in plasma IL-4, IL-5, IL-10, IL-13, and IL-17A, indicating that myricetin modulates the immune response in schistosomeinfected mice.…”

Ziziphus spina-christi leaf extract ameliorates schistosomiasis liver granuloma, fibrosis, and oxidative stress through downregulation of fibrinogenic signaling in mice

“…Li et al [ 35 ] suggested that TGF-β contributes not only in the inflammatory process, but also in the pathogenesis of human schistosomal hepatic fibrosis. Growing evidence suggests a role of TGF-β in activation of quiescent HSCs, resulting in their transdifferentiation into proliferative, fibrogenic, and contractile myofibroblasts [ 36 ]. Blockage of TGF-β signal transduction successfully inhibits the production of hepatic fibrosis [ 37 ].…”