IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica

Bai, Yifeng; Guan, Fei; Zhu, Feifan; Jiang, Chunjie; Xu, Xiaojun; Zheng, Fang; Liu, Wenqi; Lei, Jiahui

doi:10.2147/jir.s336404

Cited by 11 publications

(11 citation statements)

References 73 publications

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“…These effects of SEA on T cells and DC may act in synergy to induce Foxp3+ Treg in NOD mice ( Zaccone et al., 2009 ). In addition, inflammatory cytokines released from damaged tissues caused by eggs, such as IL-10 and IL-33, can induce Treg differentiation ( He et al., 2018 ; Bai et al., 2021 ). The components of S. japonicum egg antigens are very complex.…”

Section: Discussionmentioning

confidence: 99%

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Protective effect of Schistosoma japonicum eggs on TNBS-induced colitis is associated with regulating Treg/Th17 balance and reprogramming glycolipid metabolism in mice

Hou

Zhu

Zheng

et al. 2022

Front. Cell. Infect. Microbiol.

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Inflammatory bowel diseases (IBDs) have been classified as modern refractory diseases. However, safe, well-tolerated, and effective treatments for IBDs are still lacking. Therefore, there is an urgent need to develop novel therapeutic targets with fewer undesirable adverse reactions. A growing body of research has shown that infection with live helminths or exposure to defined helminth-derived components can downregulate pathogenic inflammation due to their immunoregulatory ability. Here we were to explore the protective role of Schistosoma japonicum eggs on murine experimental colitis caused by trinitrobenzene sulfonic acid (TNBS) and the underlying mechanism. Frequencies of splenic Treg and Th17 cells were detected by flow cytometry. Protein and mRNA expressions of Foxp3 and RORγt were investigated by Western Blot and quantitative real-time polymerase chain reaction (qPCR), respectively. Concentrations of transforming growth factor-beta1 (TGF-β1), interleukin-10 (IL-10) and IL-17A were assessed with ELISA. Expression levels of genes related to glycolipid metabolism were measured with qPCR. The results showed that pre-exposure to S. japonicum eggs contributed to the relief of colitis in the TNBS model, evidenced by improved body weight loss, reversing spleen enlargement and colon shortening, and decreased histology scores. Compared with the TNBS group, the TNBS+Egg group had increased Treg immune response, accompanied by decreased Th17 immune response, leading to the reconstruction of Treg/Th17 balance. In addition, a ratio of Treg/Th17 was correlated negatively with the histological scores in the experiment groups. Furthermore, the regulation of Treg/Th17 balance by S. japonicum eggs was associated with inhibiting the glycolysis pathway and lipogenesis, along with promoting fatty acid oxidation in the TNBS+Egg group. These data indicate that S. japonicum eggs have a protective effect against TNBS-induced colitis, which is related to restoring Treg/Th17 balance and regulating glucose and lipid metabolism.

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Section: Discussionmentioning

confidence: 99%

“…Spleen naïve CD4+ T cells (CD4 + CD25 − CD44 − CD62L + ) were sorted from the TNBS mice as previously described ( Bai et al., 2021 ). Naïve CD4+ T cells were then cultured (3×10 5 cells/well) in 96-well plates coated with anti-CD3 mAb (5 μg/mL) and soluble anti-CD28 mAb (3 μg/mL) and kept in the presence of IL-2 (100 U/mL).…”

Section: Methodsmentioning

confidence: 99%

Protective effect of Schistosoma japonicum eggs on TNBS-induced colitis is associated with regulating Treg/Th17 balance and reprogramming glycolipid metabolism in mice

Hou

Zhu

Zheng

et al. 2022

Front. Cell. Infect. Microbiol.

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“…The pathological damage and liver fibrosis in the chronic phase of schistosomiasis are caused by various immune and related cells, as well as various pro-and anti-inflammatory cytokines. 7,36,37 However, no difference was observed in the serum levels of IFN-γ, IL-2, IL-4, IL-6, IL-17 or TNF-α between the rMULT1 group and the GFP-ctl group (Figure 2A) using CBA assay. Both RT-qPCR and CBA assay detected an increase of IFN-γ expression in the livers of the rMULT1 group (Figure 2B and C).…”

Section: Overexpression Of Rmult1 Attenuates Murine Schistosomiasis A...mentioning

confidence: 95%

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

Yang¹,

Sun²,

Cao³

et al. 2022

JIR

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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, α-smooth muscle actin, TGF-β and IL-10, and upregulated expression of IFN-γ, 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-γ 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 regulating the helper T (Th)1/Th2 balance.

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“…IL-33 is a part of the IL-1 family and is normally present in the nucleus and released into the extracellular compartment in response to tissue damage ( Bai et al., 2021 ). IL-33 plays an important role in immunity to schistosome infection, and IL-33 levels are positively correlated with the progression of egg granuloma and liver fibrosis ( Zhang et al., 2021 ).…”

Section: Il-17 and Il-33 Promote Sslfmentioning

confidence: 99%

“…The tTG upregulation of IL-33 promotes liver fibrosis and worm egg granuloma ( Tang et al., 2015 ; Li et al., 2019 ). ST2 is a unique IL-33 receptor, and appropriate inhibition of IL-33/ST2 reduces the immunopathology of schistosomes; however, knockdown of IL-33 or ST2 exacerbates schistosomiasis liver pathology ( Li et al., 2019 ; Bai et al., 2021 ). IL-33 deficiency could activate excessive Th17 immune response.…”

Section: Il-17 and Il-33 Promote Sslfmentioning

confidence: 99%

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

Liu

Zhang

Liang

et al. 2022

Front. Cell. Infect. Microbiol.

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Schistosomiasis has been widely disseminated around the world, and poses a significant threat to human health. Schistosoma eggs and soluble egg antigen (SEA) mediated inflammatory responses promote the formation of egg granulomas and liver fibrosis. With continuous liver injuries and inflammatory stimulation, liver fibrosis can develop into liver cirrhosis and liver cancer. Therefore, anti-fibrotic therapy is crucial to increase the survival rate of patients. However, current research on antifibrotic treatments for schistosomiasis requires further exploration. In the complicated microenvironment of schistosome infections, it is important to understand the mechanism and pathology of schistosomiasis-associated liver fibrosis(SSLF). In this review, we discuss the role of SEA in inhibiting liver fibrosis, describe its mechanism, and comprehensively explore the role of host-derived and schistosome-derived microRNAs (miRNAs) in SSLF. Inflammasomes and cytokines are significant factors in promoting SSLF, and we discuss the mechanisms of some critical inflammatory signals and pro-fibrotic cytokines. Natural killer(NK) cells and Natural killer T(NKT) cells can inhibit SSLF but are rarely described, therefore, we highlight their significance. This summarizes and provides insights into the mechanisms of key molecules involved in SSLF development.

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IL-33/ST2 Axis Deficiency Exacerbates Hepatic Pathology by Regulating Treg and Th17 Cells in Murine Schistosomiasis Japonica

Cited by 11 publications

References 73 publications

Protective effect of Schistosoma japonicum eggs on TNBS-induced colitis is associated with regulating Treg/Th17 balance and reprogramming glycolipid metabolism in mice

Protective effect of Schistosoma japonicum eggs on TNBS-induced colitis is associated with regulating Treg/Th17 balance and reprogramming glycolipid metabolism in mice

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

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

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