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Single-cell RNA sequencing to dissect the immunological network of liver fibrosis in Schistosoma japonicum-infected mice

ABSTRACT: Liver fibrosis is a poor outcome of patients with schistosomiasis, impacting the quality of life and even survival. Eggs deposited in the liver were the main pathogenic factors of hepatic fibrosis in Schistosomiasis japonica. However, the mechanism of hepatic fibrosis in schistosomiasis remains not well defined and there is no effective measure to prevent and treat schistosome-induced hepatic fibrosis. In this study, we applied single-cell sequencing to primarily explore the mechanism of hepatic fibrosis in murine schistosomiasis japonica(n=1) and normal mouse was served as control(n=1). A total of 10,403 cells were included in our analysis and grouped into 18 major cell clusters. Th2 cells and NKT cells were obviously increased and there was a close communication between NKT cells and FASLG signaling pathway. Flow cytometry analysis indicated that the expression of Fasl in NKT cells, CD8+ T cell and NK cell were higher in SJ groups. Arg1, Retnla and Chil3, marker genes of alternatively activated macrophages (M2), were mainly expressed in mononuclear phagocyte(1) (MP(1)), suggesting that Kupffer cells might undergo M2-like polarization in fibrotic liver of schistosomiasis. CXCL and CCL signaling pathway analysis with CellChat showed that Cxcl16-Cxcr6, Ccl6-Ccr2 and Ccl5-Ccr5 were the most dominant L−R and there were close interactions between T cells and MPs. Overall, our research profiled a preliminary immunological network of hepatic fibrosis in murine schistosomiasis japonica, which might contribute to a better understanding of the mechanisms of liver fibrosis in schistosomiasis. NKT cells and CXCL and CCL signaling pathway such as Cxcl16-Cxcr6, Ccl6-Ccr2 and Ccl5-Ccr5 might be potential targets to alleviate hepatic fibrosis of schistosomiasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE220286 | GEO | 2022/12/16

REPOSITORIES: GEO

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Project description:In schistosomiasis japonica, the egg-induced granulomatous response and the development of extensive hepatic fibrosis is the main pathology. Information regarding the specific mechanisms associated with granuloma regression and the subsequent recovery events in the host liver are still limited. In this study, a murine model of schistosomiasis japonica was used to characterise the multicellular pathways occurring during liver regeneration. Schistosoma japonicum-infected C57BL/6 mice were administered with the drug praziquantel (PZQ), on a daily basis for five consecutive days to eliminate all adult parasites. The pathological changes of PZQ-treated groups after 3, 6 and 7 weeks post PZQ treatment were examined, along with the assessment of cellular infiltration to the liver. PZQ treatment significantly reduced the degree of splenomegaly, granuloma density and the collagen deposition of liver fibrosis. The infiltration of inflammatory cells, including neutrophils, eosinophils and macrophages to the liver were as well significantly decreased. Transcriptomic analysis revealed the significant up-regulation of fatty acid metabolism genes and the identification of peroxisome proliferator-activated receptor alpha (PPAR-α) as the upstream regulator during the process of liver recovery. Aryl hydrocarbon receptor (AhR) signalling pathway that is involved primarily in the regulation of hepatic enzymes responsible for xenobiotic metabolism was as well differentially up-regulated. These findings indicate that schistosome egg-induced fibrogenesis process is reversible, and provide a better understanding of the regression mechanisms associated with hepatic schistosomiasis. These results hold important implications for the future alleviation of this and other fibrotic diseases of clinical significance. C57BL/6 murine model infected with S. japonicum were treated orally with Praziquantel (PZQ) after 7 weeks post infection to examine the hepatic regression process following drug treatment. These PZQ-treated, non PZQ-treated and uninfected mice were then euthanised at 10, 13, and 14 weeks p.i. Livers were collected from each mice, and subjected to total RNA isolation and gene expression analysis. Microarray analysis of this study was performed using samples derived from 3 individual mice per group/time-point.

Project description:Schistosomiasis continues to be an important cause of parasitic morbidity and mortality world-wide. Determining the molecular mechanisms regulating the development of granulomas and fibrosis will be essential for understanding how schistosome antigens interact with the host environment. We report here the first whole genome microarray analysis of the murine liver during the progression of Schistosoma japonicum egg-induced granuloma formation and hepatic fibrosis. Our results reveal a distinct temporal relationship between the expression of chemokine subsets and the recruitment of cells to the infected liver. Genes up-regulated earlier in the response included T- and B-cell chemoattractants, reflecting the early recruitment of these cells illustrated by flow cytometry. The later phases of the response corresponded with peak recruitment of eosinophils, neutrophils, macrophages and myofibroblasts/hepatic stellate cells (HSCs) and the expression of chemokines with activity for these cells including CCL11 (eotaxin 1), members of the Monocyte-chemoattractant protein family (CCL7, CCL8, CCL12) and the Hepatic Stellate Cell/Fibrocyte chemoattractant CXCL1. Peak expression of macrophage chemoattractants (CCL6, CXCL14) and markers of alternatively-activated macrophages (e.g. Retnla) during this later phase provides further evidence of a role for these cells in schistosome-induced pathology. Additionally, we demonstrate that CCL7 immunolocalises to the fibrotic zone of granulomas. Furthermore, striking up-regulation of neutrophil markers and the localisation of neutrophils and the neutrophil chemokine S100A8 to fibrotic areas suggests the involvement of neutrophils in S. japonicum¬-induced hepatic fibrosis. These results further our understanding of the immunopathogenic and, especially, chemokine signalling pathways that regulate the development of S. japonicum-induced granulomas and fibrosis and may provide correlative insight into the pathogenesis of other chronic inflammatory diseases of the liver where fibrosis is a common feature. Keywords: Time course, disease state analysis

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Single-cell RNA sequencing to dissect the immunological network of liver fibrosis in Schistosoma japonicum-infected mice

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