Activation of primary hepatic stellate cells and liver fibrosis induced by targeting TGF-β1/Smad signaling in schistosomiasis in mice

Abstract

Background In mice, liver fibrosis is the most serious pathologic change during Schistosoma japonicum (S. japonicum) infection. Schistosomiasis is mainly characterized by schistosome egg-induced granulomatous fibrosis. Hepatic stellate cells (HSCs) are mainly responsible for the net accumulation of collagens and fibrosis formation in the liver. Activated HSCs regulated by transforming growth factor-β1 (TGF-β1)/Smad signaling have emerged as the critical regulatory pathway in hepatitis virus or carbon tetrachloride-induced liver fibrosis. However, the detailed mechanism of HSC activation in schistosome-induced liver fibrosis is poorly understood. Methods Schistosoma japonicum-induced murine models and a control group were generated by abdominal infection with 15 (± 1) cercariae. The purity of cultured primary HSCs was evaluated by immunocytochemistry. The histopathological changes in the livers of infected mice were estimated by hematoxylin–eosin and Masson staining. Dynamic expression of pro-fibrotic molecules and microRNAs was detected by real-time quantitative PCR (RT-qPCR). Mainly members involved in the TGF-β1/Smad signaling pathway were examined via RT-qPCR and Western blot. Results The egg-induced granulomatous inflammation formed at 4 weeks post-infection (wpi) and developed progressively. Alpha-smooth muscle actin (α-SMA), collagen I, collagen III, TGF-β1, Smad2, Smad3, and Smad4 showed a significant increase in mitochondrial RNA (mRNA) and protein expression compared with the control group at 7 and 9 weeks post-infection (wpi), while an opposite effect on Smad7 was observed. In addition, the mRNA expression of microRNA-21 (miRNA-21) was significantly increased at 7 wpi, and the mRNA expression of miRNA-454 was decreased starting from 4 wpi. Conclusion Our present findings revealed that HSCs regulated by the TGF-β1/Smad signaling pathway play an important role in liver fibrosis in S. japonicum-infected mice, which may provide proof of concept for liver fibrosis in schistosomiasis. Graphical Abstract

Differential Analysis of Key Proteins Related to Fibrosis and Inflammation in Soluble Egg Antigen of Schistosoma mansoni at Different Infection Times

“…It has been revealed that HSCs regulated by the TGF-β1/Smad signaling pathway play an important role in liver fibrosis in S . japonicum -infected mice [ 75 ]. TGF-β is secreted by a variety of immune cells through the Smad pathway; further promoting the elevated levels of TIMP1, α-SMA, and collagen 1/2 during the HSC to myofibroblast transition, formatting and remodeling the ECM, and eventually leading to liver fibrosis [ 76 ].…”

Diterpenoids with Schistosomula-Killing and Anti-Fibrosis Activities In Vitro from the Leaves of Croton tiglium

“…It has the effects of activating hepatic stellate cells, promoting collagen synthesis, and ultimately leading to liver fibrosis [ 10 ]. There have been multiple reports on the relationship between liver fibrosis in schistosomiasis and TGF in hepatic stellate cells-β 1 /Smads signal transduction [ 11 , 12 ].…”

Effects of Cysticercus cellulosae Excretory–Secretory Antigens on the TGF-β Signaling Pathway and Th17 Cell Differentiation in Piglets, a Proteomic Analysis

“…The transforming growth factor-β (TGF-β) signaling pathway is extremely important for regulating mammalian T lymphocyte immune responses and is mainly dependent on Smad proteins to mediate signaling [ 14 ]. Type I receptor (TβR-I) and type II receptor (TβR-II) are the receptor proteins involved in the TGF-β signaling pathway [ 15 , 16 ]. TGF-β binds to TβR-I and TβR-II receptors to form complexes that trigger intracellular signaling.…”