Toxoplasma gondii GRA15II effector-induced M1 cells ameliorate liver fibrosis in mice infected with Schistosomiasis japonica

Recent studies indicated that type II Toxoplasma gondii(Tg)GRA15II favored the generation of classically activated macrophages(M1),whereas type I/III TgROP16I/III promoted the polarization of alternatively activated macrophages(M2).A number of studies have demonstrated that M2 cells are involved in the pathogenesis of the liver fibrogenesis caused by Schistosoma japonicum.The purpose of the present study was to explore the inhibitory effect of Toxoplasma-derived TgGRA15II on mouse hepatic fibrosis with schistosomiasis.The gra15II and rop16I/III genes were amplified from strains T.gondii PRU and Chinese 1 Wh3,respectively.Lentiviral vectors containing the gra15II or rop16I/III plasmid were constructed and used to infect the RAW264.7 cell line.The polarization of the transfected cells was evaluated,followed by co-culture of the biased macrophages with mouse hepatic stellate JS1 cells.Then,mice were injected with GRA15II-driven macrophages via the tail vein and infected with S.japonicum cercariae.TgGRA15II induced a M1-biased response,whereas TgROP16I/III drove the macrophages to a M2-like phenotype.The in vitro experiments indicated that JS1 cell proliferation and collagen synthesis were decreased following co-culture with TgGRA15II-activated macrophages.Furthermore,mice inoculated with TgGRA15II-biased macrophages displayed a notable alleviation of collagen deposition and granuloma formation in their liver tissues.Our results suggest that TgGRA15II-induced M1 cells may dampen the M2 dominant pathogenesis of hepatic fibrosis and granulomatosis.These results provide insights into the use of parasite-derived immunomodulators as potential anti-fibrosis agents and to re-balance the schistosomiasis-induced immune response.

The role of macrophage reprogramming induced by GRA15II,a polypeptide effector molecule of Toxoplasma gondii,in liver diseases in model mice

Toxoplasma gondii is a widespread parasite that may infect nearly all warm-blooded vertebrates.1 As an obligatory intracellular apicomplexan parasite,T.gondii has three different types of secretory organelles,including micronemes,rhoptries(ROP),and dense granules(GRAs),during invasion of host cells.2 Initially,the parasite replicates in a variety of host cell types as tachyzoites,especially in macrophages and dendritic cells(DCs).

Paeoniflorin prevents hepatic fibrosis of Schistosomiasis japonica by inhibiting TGF-β1 production from macrophages in mice

In order to investigate the effect of paeoniflorin(PAE)on hepatic fibrosis of mice with Schistosomiasis japonica in vivo and in vitro,a model of hepatic fibrosis caused by schistosomiasis was established in mice infected with cercariae of Schistosoma japonicum.Then,PAE was orally administered before and after praziquantel treat-ment and both therapeutics were given simultaneously at different time points after the infection.The concentra-tion of serum hyaluronic acid(HA)was determined by radioimmunoassay(RIA).Hepatic granuloma and fib-rosis were evaluated via HE and Masson staining.The expression of α-smooth muscle actin(α-SMA),transform-ing growth factor β1(TGF-β1)and collagen I(Col I)protein was detected by immunohistochemistry.The effect of soluble egg antigen(SEA)and PAE on the pro-duction of TGF-β1 from mouse peritoneal macrophages(PMQs)was investigated by RT-PCR,Western blotting and ELISA.The effect of TGF-β1 in optimum macro-phage-conditioned medium(OPMCM)on the prolifera-tion of hepatic stellate cells(HSCs)and collagen secretion from HSCs with anti-TGF-β1 antibody was explored by MTT assay and ELISA.The results show that PAE could significantly reduce the concentration of serum HA,the size of egg granuloma,the severity of hepatic fibrosis and the expression of a-SMA,TGF-β1 and Col I protein in the pre-treatment group.However,in sim-or post-treatment group,PAE did not have any significant therapeutic effect.TGF-β1 could be secreted from PMQs stimulated by SEA.Meanwhile,the production of TGF-β1 from PMQs could be depressed significantly by PAE in a con-centration-dependent manner.TGF-β1 could promote the proliferation of HSCs and the secretion of collagens.In a word,PAE can prevent hepatic granuloma and fib-rosis caused by schistosomiasis japonica through the inhibition of the secretion of TGF-β1 from PMQs,the proliferation and activation of HSCs and the secretion of collagens from HSCs.