Dataset Information

MicroRNA-21 Mediates the Inhibiting Effect of Praziquantel on NLRP3 Inflammasome in Schistosoma japonicum Infection.

ABSTRACT: Praziquantel (PZQ), a traditional helminthicide drug, has been shown to exert an anti-inflammatory effect on splenomegaly induced by schistosomiasis via regulating macrophage polarization. Meanwhile, miR-21 has been demonstrated to control macrophage polarization. However, the role of miR-21 in the regulation of macrophage polarization by PZQ in schistosomiasis is still unclear. In the present study, we found that M1-type macrophages were the predominant splenic macrophages in chronic schistosomiasis and that NLRP3 inflammasome-related molecules were upregulated. PZQ inhibited NLRP3 inflammasome in M1 macrophages and reduced the expression of miR-21. Furthermore, using the methods of quantitative real-time PCR and transfection, the downregulation of NLRP3/IL-1? by PZQ in M1 macrophages were reversed by miR-21 overexpression. These results indicated that miR-21 was involved in the inhibiting effect of PZQ on activation of NLRP3 inflammasome. Moreover, miR-21 might target Smad7 to mediate the anti-inflammatory effect of PZQ in polarized macrophages. This study provides an in-depth mechanism of PZQ in the treatment of schistosomiasis.

SUBMITTER: Kong D

PROVIDER: S-EPMC7029728 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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MicroRNA-21 Mediates the Inhibiting Effect of Praziquantel on NLRP3 Inflammasome in <i>Schistosoma japonicum</i> Infection.

Kong Delong D Guo Hongfei H Lu Zhongkui Z Cui Jie J

Frontiers in veterinary science 20200212

Praziquantel (PZQ), a traditional helminthicide drug, has been shown to exert an anti-inflammatory effect on splenomegaly induced by schistosomiasis via regulating macrophage polarization. Meanwhile, miR-21 has been demonstrated to control macrophage polarization. However, the role of miR-21 in the regulation of macrophage polarization by PZQ in schistosomiasis is still unclear. In the present study, we found that M1-type macrophages were the predominant splenic macrophages in chronic schistosom ...[more]

PMID: 32118052

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Project description:BackgroundSchistosomiasis is a parasitic disease infecting more than 200 million people in the world. Although chemotherapy targeting on killing schistosomes is one of the main strategies in the disease control, there are few effective ways of dealing with liver fibrosis caused by the parasite infection in the chronic and advanced stages of schistosomiasis. For this reason, new strategies and prospective drugs, which exert antifibrotic effects, are urgently required.Methods and findingsThe antifibrotic effects of praziquantel were assessed in the murine models of schistosomiasis japonica. Murine fibrosis models were established by cutaneous infection with 14 ± 2 Schistosoma japonicum cercariae. Then, the mice of both chronic (8 weeks post-infection) and advanced (15 weeks post-infection) schistosomiasis were treated by gavage of praziquantel (250 mg/kg, once daily for 3 days) to eliminate worms, and followed by praziquantel anti-fibrosis treatment (300 mg/kg, twice daily for 30 days). The fibrosis-related parameters assessed were areas of collagen deposition, content of hydroxyproline and mRNA expressions of Col1?1, Col3?1, ?-SMA, TGF-?, MMP9, TIMP1, IL-4, IL-10, IL-13 and IFN-? of liver. Spleen weight index, alanine aminotransferase activity and liver portal venous pressure were also measured. The results showed that anti-fibrosis treatment improved liver fibrosis, splenomegaly, hepatic function, as well as liver portal hypertension. In order to confirm the anti-fibrotic properties of praziquantel, we established a CCL(4)-induced model and revealed that CCL(4)-induced liver fibrosis was inhibited by PZQ treatment for 30 days. Furthermore, we analyzed the effects of praziquantel on mouse primary hepatic stellate cells (HSCs). It is indicated that mRNA expressions of Col1?1, Col3?1, ?-SMA, TGF-?, MMP9 and TIMP1 of HSCs were all inhibited after praziquantel anti-parasite treatments.ConclusionsThe significant amelioration of hepatic fibrosis by praziquantel treatment validates it as a promising drug of anti-fibrosis and offers potential of a new chemotherapy for hepatic fibrosis resulting from schistosomiasis.

Project description:BackgroundSchistosomiasis japonica remains a significant public health problem in China and Southeast Asian countries. The most typical and serious outcome of the chronic oriental schistosomiasis is the progressive granuloma and fibrosis in the host liver, which has been a major medical challenge. However, the molecular mechanism underling the hepatic pathogenesis is still not clear.Methodology and principal findingsUsing microarrays, we quantified the temporal gene expression profiles in the liver of Schistosoma japonicum-infected BALB/c mice at 15, 30, and 45 day post infection (dpi) with that from uninfected mice as controls. Gene expression alternation associated with liver damage was observed in the initial phase of infection (dpi 15), which became more magnificent with the onset of egg-laying. Up-regulated genes were dominantly associated with inflammatory infiltration, whereas down-regulated genes primarily led to the hepatic functional disorders. Simultaneously, microRNA profiles from the same samples were decoded by Solexa sequencing. More than 130 miRNAs were differentially expressed in murine liver during S. japonicum infection. MiRNAs significantly dysregulated in the mid-phase of infection (dpi 30), such as mmu-miR-146b and mmu-miR-155, may relate to the regulation of hepatic inflammatory responses, whereas miRNAs exhibiting a peak expression in the late phase of infection (dpi 45), such as mmu-miR-223, mmu-miR-146a/b, mmu-miR-155, mmu-miR-34c, mmu-miR-199, and mmu-miR-134, may represent a molecular signature of the development of schistosomal hepatopathy. Further, a dynamic miRNA-gene co-expression network in the progression of infection was constructed.Conclusions and significanceThis study presents a global view of dynamic expression of both mRNA and miRNA transcripts in murine liver during S. japonicum infection, and highlights that miRNAs may play a variety of regulatory roles in balancing the immune responses during the development of hepatic pathology. The data provide robust information for further researches on the pathogenesis and molecular events of hepatopathy induced by schistosome eggs.

Project description:BACKGROUND:NOD-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. METHODS:BALB/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. RESULTS:NLRP3 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-1?, ALT/AST in plasma, and NF-?B 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. CONCLUSIONS:MCC950 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-?B. 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.

Dataset Information

MicroRNA-21 Mediates the Inhibiting Effect of Praziquantel on NLRP3 Inflammasome in Schistosoma japonicum Infection.

Publications

MicroRNA-21 Mediates the Inhibiting Effect of Praziquantel on NLRP3 Inflammasome in <i>Schistosoma japonicum</i> Infection.

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