NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner

Lü, Yanjun; Zhong, Sen; Meng, Nan; Fan, Yin-Ping; Tang, Wang-Xian

doi:10.1038/s41598-017-08689-1

Cited by 29 publications

(36 citation statements)

References 47 publications

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“…Following this seminal study, NLRP3 inflammasome role has been investigated, especially in S. japonicum infection. In this context, NLRP3 has been shown to be pivotal for inducing hepatic granuloma formation and collagen deposition in the granulomatous structure (18,43). In this study, we confirmed that NLRP3 is pivotal for hepatic granuloma formation, but we did not find any alteration in collagen deposition in Nlrp3 −/− mice when compared to WT (Supplementary Figure S7).…”

Section: Discussionsupporting

confidence: 73%

“…The inflammasome pathway plays an essential role in schistosomiasis-associated liver pathology. It has been demonstrated that NLRP3 is critical for granuloma formation and hepatic stellate cells (HSCs) activation (18) in S. japonicum infections. Regarding S. mansoni infection this same sensor has been shown to be involved in the adaptive immune response and also granuloma formation (9).…”

Section: Introductionmentioning

confidence: 99%

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NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

et al. 2020

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Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1β production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6 −/− mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1 −/− , IL-1R −/− and Gsdmd −/− mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

et al. 2020

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“…Growing evidence has linked NLRP3 inflammasome-driven inflammation to tissue damage and liver fibrosis in conditions such as drug-induced liver injury, alcoholic steatohepatitis (ASH) and angiotensin II (Ang-II) [20, 21]. In fact, recent studies have found that NLRP3 inflammasome is present in liver fibrosis induced by S. japonicum infection [17, 22]. NLRP3 inflammasome is composed of NLRP3 protein, apoptosis associated speck-like protein (ASC) and pro-caspase I [19, 23].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, a large number of studies focus on NLRP3 inflammasome expression and its activation mechanisms [35, 36] but few have examined how NLRP3 inflammasome regulates liver fibrosis [7, 22]. Here, we aim to provide more data to deeply understand the effects of NLRP3 on the process of liver fibrosis in schistosomiasis.…”

Section: Introductionmentioning

confidence: 99%

NLRP3 inflammasome activation from Kupffer cells is involved in liver fibrosis of Schistosoma japonicum-infected mice via NF-κB

2019

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BackgroundNOD-like receptor protein 3 (NLRP3) inflammasome was reported as expressed in schistosomiasis-induced liver fibrosis (SSLF). We used an NLRP3 inflammasome inhibitor, MCC950, to investigate whether it inhibited liver fibrosis, and explored the preliminary molecular mechanism.MethodsBALB/c mice were infected with 15 cercariae through the abdominal skin. They received intraperitoneal injections of MCC950 on the day of infection and at day 22 post-infection. We examined their SSLF phenotype and the effect on liver fibrosis, primary Kupffer cells (KCs), and HSCs. Human hepatic stellate cell lines (human LX-2 cells) were treated with soluble egg antigen (SEA) released from the eggs. We then determined the expression of NLRP3 inflammasome and liver fibrosis-associated markers, liver granuloma and ALT/AST.ResultsNLRP3 inflammasome expression in the liver was significantly increased, and eosinophilic granuloma and collagen deposition were found around the eggs in mice infected for 56 days. Additionally, IL-1β, ALT/AST in plasma, and NF-κB in liver tissue and in KCs were all greatly significantly increased. The above-mentioned indicators were largely reduced in mice treated with MCC950 on the day of infection. In vitro, lipopolysaccharide (LPS)/SEA could induce LX-2 cells to express NLRP3 and fibrosis markers, and the SEA-treated group was reversed by MCC950. Furthermore, NLRP3 inflammasome and liver fibrosis-associated markers were both increased in the primary KCs and HSCs isolated from infected mice. However, this effect was not observed in the same cells from the mice treated with MCC950 on the day of infection. Contrary to the aforementioned results, MCC950 treatment at day 22 post-infection aggravated this process. Surprisingly, NLRP3 inflammasome was involved in liver fibrosis mostly from KCs.ConclusionsMCC950 acts dually on SSLF pathology and fibrosis in infected mice. Although MCC950 treatment improved SSLF on the day of infection, it exacerbated the pathological effects at day 22 post-infection. These dual effects were mediated via NF-κB. Moreover, NLRP3 inflammasome mainly came from KCs. Our results suggest that blocking NLRP3 on the day of infection may prove to be a promising direction in preventing SSLF.

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“…Numerous studies have demonstrated that Syk-mediated mitogen-activated protein kinases play a vital role in the expression of inflammatory genes [ 31 – 33 ]. Syk mediates NLRP3 inflammasome activation [ 34 – 36 ]. Therefore, one can infer that by inhibiting the phosphorylation of Syk, LA inhibits the activity of p38/JNK and reduces both the expression of NLRP3 and the secretion of related proteins IL-1 β and IL-18 ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

Levistilide A Ameliorates NLRP3 Expression Involving the Syk-p38/JNK Pathway and Peripheral Obliterans in Rats

Guo

Sun

Ling

et al. 2018

Mediators of Inflammation

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Background Inflammation is one of the most important pathogeneses of thromboangiitis obliterans (TAO). The NLRP3 inflammasome plays a vital role in the body's immune response and disease development. It can be activated by numerous types of pathogens or danger signals. As the core of the inflammatory response, the NLRP3 inflammasome may provide a new target for the treatment of various inflammatory diseases. Levistilide A (LA) is a phthalide dimer isolated from umbelliferous plants. Its pharmacological effect is largely unknown. This study revealed the effects of LA on endothelial cell activation, NLRP3, IL-1β, TNF-α, IL-32, and CCL-2, VCAM-1, MCP-1, and the spleen tyrosine kinase (Syk)--p38/JNK signaling axis and its effect on vasculitis in rats. Results LA inhibited endothelial activation and the expression of IL-1β, TNF-α, IL-32, CCL-2, VCAM-1, and MCP-1. LA directly obstructed Syk phosphorylation and activity in a dose-dependent manner, inhibited the activity of p38 and JNK, and reduced the expression of NLRP3 in human umbilical vein endothelial cells and vascular tissue of rats with vasculitis. Conclusion LA suppressed NLRP3 gene expression by blocking the Syk--p38/JNK pathway and reduced damage to the rats' limbs in the thromboangiitis obliterans model.

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NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner

Cited by 29 publications

References 47 publications

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection

NLRP3 inflammasome activation from Kupffer cells is involved in liver fibrosis of Schistosoma japonicum-infected mice via NF-κB

Levistilide A Ameliorates NLRP3 Expression Involving the Syk-p38/JNK Pathway and Peripheral Obliterans in Rats

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