Soluble Egg Antigens of Schistosoma japonicum Induce Senescence of Activated Hepatic Stellate Cells by Activation of the FoxO3a/SKP2/P27 Pathway

Background Liver fibrosis was viewed as a reversible process. The activation of hepatic stellate cells (HSCs) is a key event in the process of liver fibrosis. The induction of senescence of HSCs would accelerate the clearance of the activated HSCs. Previously, we demonstrated that soluble egg antigens (SEA) of Schistosoma japonicum promoted the senescence of HSCs via STAT3/P53/P21 pathway. In this paper, our study was aimed to explore whether there are other signaling pathways in the process of SEA-induced HSCs aging and the underlying effect of SKP2/P27 signal on senescent HSCs. Methodology/Principal findings Human hepatic stellate cell line, LX-2 cells, were cultured and stimulated with SEA. Western blot and cellular immunofluorescence analysis were performed to determine the expression of senescence-associated protein, such as P27, SKP2 and FoxO3a. Besides, RNA interfering was applied to knockdown the expression of related protein. The senescence of HSCs was determined by senescence-associated β-gal staining. We found that SEA increased the expression of P27 protein, whereas it inhibited the expression of SKP2 and FoxO3a. Knockdown of P27 as well as overexpression of SKP2 both suppressed the SEA-induced senescence of HSCs. In addition, the nuclear translocation of FoxO3a from the nucleus to the cytoplasm was induced by SEA stimulation. Conclusions/Significance The present study demonstrates that SEA promotes HSCs senescence through the FoxO3a/SKP2/P27 pathway.
Author Summary Activation of hepatic stellate cells (HSCs) is a key event of liver fibrosis. Induction of activated HSCs apoptosis and inhibition of activated HSCs proliferation are the common anti-fibrotic strategies to block liver fibrosis. The induction of senescence of HSCs is responsible for the clearance of the activated HSCs as well. Senescence of HSCs is mediated by exposure to soluble egg antigens (SEA) of Schistosoma japonicum via STAT3/P53/P21 pathway. In this study, we found that SEA induced the senescence of HSCs, accompanied with the increased the expression of P27 protein and the decreased expression of SKP2 and FoxO3a. Either knockdown of P27 or overexpression of SKP2 alleviates the SEA-induced senescence of HSCs. Moreover, SEA droved the nuclear translocation of FoxO3a from the nucleus to the cytoplasm. Hence, the present study demonstrates that SEA promotes HSCs senescence through the FoxO3a/SKP2/P27 pathway.