CXCR6 recruits Th2 cells and promotes liver fibrosis in schistosomiasis japonica.

Abstract

Background: Schistosomiasis is a parasitic disease that significantly endangers human health and hampers social development. The accumulation of eggs in the liver can lead to granuloma formation and liver fibrosis. Investigating the immune mechanisms involved may reveal new therapeutic targets for schistosomiasis.

Methods: We collected liver cells from both schistosome-infected mice with fibrotic livers and healthy mice for single-cell sequencing, which allowed us to explore the heterogeneity of immune cells in the fibrotic livers and to use ligand-receptor analysis to examine intercellular communication.

Results: Single-cell sequencing showed significant upregulation of the CXCL16-CXCR6 axis in the fibrotic livers of schistosome-infected mice. Macrophages were the primary source of CXCL16, while CXCR6 was predominantly expressed in T cells. CD4+ T cells and CD8+ T cells were significantly increased in the livers of schistosomiasis, as well as CXCR6 in CD4+T cells and CD8+ T cells. Among different T-cell subsets, Th2 cells primarily expressed the chemokine receptor CXCR6. In CXCR6KO mice, we observed a reduced granuloma area and diminished liver fibrosis. CD4+ T cells were notably lower in the livers of CXCR6KO mice compared to wild-type mice, although there were no significant differences in CD8+ T cells and NKT cells. Furthermore, Th2 cells in the livers of CXCR6KO mice were markedly reduced, along with significant decreases in IL-13, IL-5, and IL-4 levels. In vitro, CXCR6 was significantly upregulated under Th2-polarizing conditions.

Conclusions: Th2 cells are recruited to the liver via the CXCL16-CXCR6 axis, promoting granuloma formation and liver fibrosis in schistosomiasis. The CXCR6 pathway holds potential as a therapeutic target for treating schistosome-associated liver fibrosis.