Negative Regulation of Schistosoma japonicum Egg-Induced Liver Fibrosis by Natural Killer Cells

Abstract

The role of natural killer (NK) cells in infection-induced liver fibrosis remains obscure. In this study, we elucidated the effect of NK cells on Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis. Liver fibrosis was induced by infecting C57BL/6 mice with 18–20 cercariae of S. japonicum. Anti-ASGM1 antibody was used to deplete NK cells. Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid (poly I∶C) was used to enhance the activation of NK cells. Results showed that NK cells were accumulated and activated after S. japonicum infection, as evidenced by the elevation of CD69 expression and IFN-γ production. Depletion of NK cells markedly enhanced S. japonicum egg-induced liver fibrosis. Administration of poly I∶C further activated NK cells to produce IFN-γ and attenuated S. japonicum egg-induced liver fibrosis. The observed protective effect of poly I∶C on liver fibrosis was diminished through depletion of NK cells. Disruption of IFN-γ gene enhanced liver fibrosis and partially abolished the suppression of liver fibrosis by poly I∶C. Moreover, expression of retinoic acid early inducible 1 (RAE 1), the NKG2D ligand, was detectable at high levels on activated hepatic stellate cells derived from S. japonicum-infected mice, which made them more susceptible to hepatic NK cell killing. In conclusion, our findings suggest that the activated NK cells in the liver after S. japonicum infection negatively regulate egg-induced liver fibrosis via producing IFN-γ, and killing activated stellate cells.

Natural killer cells in liver disease

“…NK cell killing of activated HSCs was first demonstrated by two different groups using mouse models in 2006, which play an important role in inhibiting liver fibrosis; 8, 9 these results were later confirmed in other mouse models of liver fibrosis. 7, 65, 66 The important antifibrotic functions of NK cells were also recently demonstrated in HCV patients by several clinical studies. 5‐7 First, in vitro coculture of activated primary human HSCs with human NK cells resulted in the killing of the HSCs by the production of TRAIL and FasL.…”

The Immunology of Fibrosis

“…In chronic schistosomiasis, a downregulation of the immune reaction can be observed (66). B cells (67) and a pathway dependent on the stimulation of the IL-13 receptor α2 (68) as well as activated IFN-γ-producing NK cells (69) have been suggested as being responsible for this downregulation. Finally, HSCs stimulated by cytokines, including TGF-β1 produced by Th2 cells responding to schistosome antigens, transdifferentiate into myofibroblasts, producing excessive amounts of type III, VI, and I collagen (63,70).…”

Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients

“…Particularly, natural killer (NK) cells, being abundant in the liver and serving as the major innate immune component against infection and tumours10, also play an important role in inhibiting liver fibrosis1112. These results were later confirmed in other mouse models of liver fibrosis131415 and in HCV patients by several clinical studies141617. Taken together, these studies suggested that the host could orchestrate highly complex immune responses to regulate liver fibrogenesis during chronic virus infection.…”