Immunopathology in schistosomiasis is regulated by TLR2,4- and IFN-γ-activated MSC through modulating Th1/Th2 responses

Abstract

Background and aims: A marked egg-induced CD4 + T cell programmed inflammation and subsequent hepatic fibrosis characterize the pathogenesis of schistosomiasis. Mesenchymal stem cell (MSC) has been extensively studied for the treatment of schistosomiasis. However, the mechanism by which MSCs modulate the pathogenesis of schistosomiasis has not been clarified. Furthermore, the local inflammatory milieu may greatly influence the immunoregulatory properties of MSCs, and our early experiments demonstrated that Toll-like receptor (TLR)2/TLR4 agonist effected immune modulation of MSC. Here, we further investigated their modulation on the pathogenesis of schistosomiasis. Methods: Adult BALB/c male mice were percutaneously infected with 16 ± 2 pairs S. japonicum cercariae and received intravenously pretreated MSC at 1 week and 3 weeks post-infection, respectively. At 8 weeks post-infection, effects of MSC on liver histology were shown by hematoxylin and eosin (H&E) staining and Masson staining and quantitatively compared by the hepatic hydroxyproline content; α-smooth muscle actin (α-SMA), collagen type I(Col-1), transforming growth factor β (TGF-β), and tumor necrosis factor-α (TNF-α) gene expression in the liver were assessed by semi-quantitative polymerase chain reaction (PCR); the Th1/Th2 dominance among different groups was compared by analyzing CD4 + interferon-γ (IFN-γ)+ and CD4+interleukin-4 (IL-4)+T cells in the liver by flow cytometry and serum level of IFN-γ and IL-5 using enzyme-linked immunosorbent assay (ELISA). Effects of different kinds of MSC were further evaluated in vitro by the coculture system. Results: Results showed TLR4-and IFN-γ-activated MSC alleviated liver fibrosis in infected mice, without a significant increase of mortality, and unpretreated MSC showed no clear improvement; however, TLR2-and IFN-γactivated MSC displayed aggravated immunopathology. In accord with the pathological results, TLR4-and IFN-γactivated MSC groups showed moderate enhancement of Th1 response in vitro and clear Th1 dominance in vivo without leading to extreme inflammation, whereas TLR2-and IFN-γ-activated MSC not only induced Th1 response, but also triggered excessive inflammation as evidenced by atrophy of the thymus and higher TNF level in the coculture system.

Application of TGF‑β1, TIMP‑1 and TIMP‑2 small interfering RNAs can alleviate CCl4‑induced hepatic fibrosis in rats by rebalancing Th1/Th2 cytokines

“…The results of the present study suggested that the expression levels of IL-4 and IL-13 in rats with hepatic fibrosis induced by CCl 4 were significantly increased compared with those in normal rats, and the expression of IFN-γ was decreased. This finding is consistent with the results of previous studies, such as in hepatic fibrosis induced by schistosomiasis (11,20). Treatment with TGF-β1 siRNA reduced the degree of hepatic fibrosis, but the expression levels of IL-4 and IL-13 in the liver were not significantly reduced compared with those of the model group.…”

“…IFN-γ is an important Th1 factor, as it promotes the differentiation of Th1 cells and inhibits the differentiation of Th2 cells (11). IFN-γ can inhibit the activation and proliferation of myofibroblasts and promote their apoptosis, thereby suppressing the production of ECM (12).…”

Chlorogenic acid ameliorated allergic rhinitis-related symptoms in mice by regulating Th17 cells

“…Our finding indicated that the anti-AR effect of CGA may be closely related to the inhibition of TH17 differentiation. IFN-γ, a Th1 cell cytokine can suppress Th2 cell proliferation to affect Th1/Th2 balance and induce macrophage production [ 46 , 47 ]. Increased level of IFN-γ contributes to shifting from Th2 to Th1 [ 48 ].…”

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

“…The TLR family consists of 13 molecules that are widely expressed on immune and non-immune cells in mice. Of these, TLR2/4 is the most important receptor for the recognition of schistosome components ( Zhang et al., 2011 ; Liu et al., 2020 ). However, TLR2 and TLR4 have different effects on schistosome infection.…”