Abstract
Hepatic fibrosis induced by egg deposition is the most serious pathology associated with chronic schistosomiasis, in which the hepatic stellate cell (HSC) plays a central role. While the effect of Schistosoma mansoni eggs on the fibrogenic phenotype of HSCs has been investigated, studies determining the effect of eggs of S . japonicum on HSCs are lacking. Disease caused by S . japonicum is much more severe than that resulting from S. mansoni infection so it is important to compare the pathologies caused by these two parasites, to determine whether this phenotype is due to the species interacting differently with the mammalian host. Accordingly, we investigated the effect of S . japonicum eggs on the human HSC cell line, LX-2, with and without TGF-β (Transforming Growth Factor beta) co-treatment, so as to determine the impact on genes associated with fibrogenesis, inflammation and matrix re-organisation. Activation status of HSCs was assessed by αSMA (Alpha Smooth Muscle Actin) immunofluorescence, accumulation of Oil Red O-stained lipid droplets and the relative expression of selected genes associated with activation. The fibrogenic phenotype of HSCs was inhibited by the presence of eggs both with or without TGF-β treatment, as evidenced by a lack of αSMA staining and reduced gene expression of αSMA and Col1A1 (Collagen 1A1). Unlike S. mansoni-treated cells, however, expression of the quiescent HSC marker PPAR-γ (Peroxisome Proliferator-Activated Receptor gamma) was not increased, nor was there accumulation of lipid droplets. In contrast, S . japonicum eggs induced the mRNA expression of MMP-9 (Matrix Metalloproteinase 9), CCL2 (Chemokine (C-C motif) Ligand 2) and IL-6 (Interleukin 6) in HSCs indicating that rather than inducing complete HSC quiescence, the eggs induced a proinflammatory phenotype. These results suggest HSCs in close proximity to S . japonicum eggs in the liver may play a role in the proinflammatory regulation of hepatic granuloma formation.
Highlights
Schistosomiasis is the most important of the human helminthiases, estimated to infect 200 million people resulting in a loss of millions of disability-adjusted life-years (DALYs) per annum [1,2,3]
These results indicate that while the genes associated with the profibrogenic phenotype of hepatic stellate cell (HSC) were down-regulated by S. japonicum eggs, a switch to a fully quiescent phenotype did not occur as evidenced by the unchanged expression of PPARγ
This study demonstrates for the first time a specific granuloma regulatory phenotype in HSCs caused directly by interaction with soluble mediators produced by eggs of the parasite S. japonicum
Summary
Schistosomiasis is the most important of the human helminthiases, estimated to infect 200 million people resulting in a loss of millions of disability-adjusted life-years (DALYs) per annum [1,2,3]. The HSC is one of the main cells contributing to fibrosis within the liver and has a contributory role in collagen production in murine and human S. japonicum infections [9] and human S. mansoni infection [10]. In response to insult or injury, HSCs undergo a process of transdifferentiation, becoming fibrogenic myofibroblasts responsible for collagen production and accumulation of a scarlike matrix [12]. This process is well understood in vitro with primary HSCs undergoing spontaneous activation in normal cell culture conditions, which has allowed the identification of markers of activation status. The response to TGF-β is well documented and is used as an in vitro model for HSC activation [20,21] and previously on LX-2 cells [16]
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