Inhibition of hepatic natural killer cell function via the TIGIT receptor in schistosomiasis-induced liver fibrosis

Schistosomiasis is a zoonotic parasitic disease. Schistosoma japonicum eggs deposited in the liver tissue induce egg granuloma formation and liver fibrosis, seriously threatening human health. Natural killer (NK) cells kill activated hepatic stellate cells (HSCs) or induce HSC apoptosis and inhibit the progression of liver fibrosis. However, the function of NK cells in liver fibrosis caused by S. japonicum infection is significantly inhibited. The mechanism of this inhibition remains unclear. Twenty mice were percutaneously infected with S. japonicum cercariae. Before infection and 2, 4, 6, and 8 weeks after infection, five mice were euthanized and dissected at each time point. Hepatic NK cells were isolated and transcriptome sequenced. The sequencing results showed that Tigit expression was high at 4-6 weeks post infection. This phenomenon was verified by reverse transcription quantitative PCR (RT-qPCR) and flow cytometry. NK cells derived from Tigit(-/-) and wild-type (WT) mice were co-cultured with HSCs. It was found that Tigit(-/-) NK cells induced apoptosis in a higher proportion of HSCs than WT NK cells. Schistosomiasis infection models of Tigit(-/-) and WT mice were established. The proportion and killing activity of hepatic NK cells were significantly higher in Tigit(-/-) mice than in WT mice. The degree of liver fibrosis in Tigit(-/-) mice was significantly lower than that in WT mice. NK cells were isolated from Tigit(-/-) and WT mice and injected via the tail vein into WT mice infected with S. japonicum. The degree of liver fibrosis in mice that received NK cell infusion reduced significantly, but there was no significant difference between mice that received NK cells from Tigit(-/-) and WT mice, respectively. Our findings indicate that Tigit knockout enhanced the function of NK cells and reduced the degree of liver fibrosis in schistosomiasis, thus providing a novel strategy for treating hepatic fibrosis induced by schistosomiasis. Author summarySchistosomiasis is a serious zoonotic parasitic disease. Schistosoma japonicum egg deposition in the liver induces granuloma formation and liver fibrosis, which are the main causes of death in patients with chronic and advanced schistosomiasis. Identifying the regulatory mechanism of liver fibrosis in schistosomiasis is crucial to inhibiting its progression. Natural killer (NK) cells kill activated hepatic stellate cells or induce their apoptosis and stop the progression of liver fibrosis. We found that TIGIT, an inhibitory receptor, was significantly highly expressed on NK cells at 4 and 6 weeks post infection, which may be associated with NK cell inhibition in schistosomiasis. We further explored the role of the TIGIT receptor in regulating NK cell-killing activity and liver fibrosis in schistosomiasis. Results indicate that blocking TIGIT receptors activated NK cells and decreased the extent of liver fibrosis, providing a novel target for treating liver fibrosis in schistosomiasis.