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.