TLR2/4-activated MSC Regulating Immunopathology In Schistosomiasis Japonica Through Modulating Th1/Th2 Responses

Background & Aims: A marked egg-induced CD4+ T-cell programmed granulomatous inflammation and subsequent hepatic fibrosis characterize the pathogenesis of schistosomiasis.Mesenchymal stem cell(MSC)has been searched for treatment of schistosomiasis.However,the mechanism how MSCs modulate pathogenesis of schistosomiasis has not been clarified.Furthermore,the local inflammatory milieu may greatly influence the immunoregulatory properties of MSCs.Our in vitro experiment showed TLR2/TLR4 agonist combined with IFN-? clearly increased key mediators(i NOS and IL-6)expression of MSC.Their modulation on pathogenesis of schistosomiasis japonica was further investigated.Methods: Adult BALB/c male mice were percutaneously infected with 16±2 pairs of Schistosome japonicum cercariae and intravenously treated with different pretreated MSC at 2week and 4 week post infection,respectively.At 8 week post infection,effects of MSC on liver histology were displayed by HE staining and Masson staining and quantitatively compared by the hepatichydroxyproline content;?-SMA,Col-1and TGF-? expression in the liver were assessed by Real-time PCR;the Th1/Th2 dominance among different groups were compared by analyzing CD4+IFN-?+ and CD4+IL-4+T cells in the liver by flow cytometry and serum level of IFN-? and IL-5 by ELISA.Effects of different kinds of MSC were further evaluated in vitro coculture system.Results: Results revealed that TLR4-activated MSC alleviated liver granulomatous and fibrosis in infected mice,without significant increase of mortality;and unpretreated MSC showed no clear improvement;however,TLR2-activated MSC displayed aggravated immunopathology.In accordance with the pathological results,TLR4-activated MSC group demonstrated moderate enhancement of Th1 response in vitro and clear Th1 dominance in vivo without leading to extreme inflammation.Whereas,TLR2-activated MSC not only induced Th1 response,but also triggered excessive inflammation evidenced by atrophy of thymus and high TNF level in the coculture system.Conclusions: This study demonstrates that only TLR4 activated MSC group did show positive effects on pathology of schistosomasis japonica by modulating Th subsets to some extent.The above findings suggested that subtle pretreatment method of MSC should be taken into consideration when using MSC to treat different immuno-disturbance diseases.