MULT1-Encoding DNA Alleviates Schistosomiasis-Associated Hepatic Fibrosis via Modulating Cellular Immune Response

Purpose: In schistosomiasis-associated hepatic fibrosis, the role of murine UL16-binding protein-like transcript 1 (MULT1), the strongest ligand of natural killer group 2-member D receptor (NKG2D), remains unclear. Here, Schistosoma japonicum-infected mice administered with MULT1-encoding DNA were used to test MULT1 as a potential therapy for schistosomiasis-associated hepatic fibrosis and explore relevant mechanisms. Materials and Methods: A recombinant plasmid encoding MULT1 (p-rMULT1) was constructed and administered to Schistosoma japonicum-infected BALB/c mice via hydrodynamic tail vein injection. Egg granulomas in liver, hepatic fibrosis biomarkers and levels of cytokines were investigated. Comparisons of CD4+ T, CD8+ T, NK and NKT proportions as well as their phenotype were performed not only between Schistosoma infected, p-rMULT1 treated group and Schistosoma infected, backbone plasmid pEGFP-N1 treated group but also between infected, nontreated group and health control group. Results: Reduced area of granuloma formation and fibrosis around single eggs, downregulated expression of collagen I, alpha-smooth muscle actin, TGF-beta and IL-10, and upregulated expression of IFN-gamma, were observed in the livers of p-rMULT1 treated mice. p-rMULT1 treatment improved Schistosoma infection impacted immune microenvironment by modulating proportion of CD4(+) T CD8(+) T, natural killer (NK) and NKT cells, enhancing expression of NKG2D, in lymphocytes, and augmenting IFN-gamma secretion by CD4(+)T, CD8(+) T, NK and NKT cells, as well as partially reversing some other phenotype changes of lymphocytes. Conclusion: To the best of our knowledge, we provided the first in vivo evidence that MULT1 is a favorable anti-fibrosis factor in the context of schistosomiasis. The inhibitory effect of MULT1 overexpression on schistosomiasis associated with hepatic fibrosis may result from augmenting the proportion and function of NKG2D-expressing immune cells, and from enhancing NK-and T-cell activation, as well as the T balance.

Automated summary

This study provides the first in vivo evidence that MULT1 is a favorable anti-fibrosis factor in the context of schistosomiasis-associated hepatic fibrosis. By modulating the proportion and function of immune cells, MULT1 can improve the immune microenvironment affected by schistosomiasis infection and inhibit liver fibrosis.