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METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway.

ABSTRACT: Hepatic fibrosis (HF) is caused by chronic hepatic injury and is characterized by hepatic stellate cells (HSCs) activation. Studies focusing on the function of exosomes derived from macrophages in HF progression are limited. This study aims to identify the roles of exosomal NEAT1 derived from macrophages on HF and the underlying mechanisms. Our studies showed that METTL3 targeted and enhanced NEAT1 expression in macrophages. Exosomal NEAT1 originating from LPS-treated macrophages promoted HSCs proliferation and migration, and induced the expression of fibrotic proteins including collagen I, α-SMA, and fibronectin. Macrophage exosomal NEAT1 contributed to HSCs activation by sponging miR-342. MiR-342 directly targeted Sp1 and suppressed its downstream TGF-β1/Smad signaling pathway, which eventually led to the inhibition of HSCs activation. Depletion of NEAT1 in the macrophage exosomes inhibited HF progression both in vitro and in vivo. Altogether, our study proved that silence of NEAT1 in the macrophage exosomes exerted protective roles against HF through the miR-342/Sp1/TGF-β1/Smad signaling pathway, suggesting a potential therapeutic target in HF treatment.

SUBMITTER: Shu B

PROVIDER: S-EPMC9117676 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway.

Shu Bo B Zhang Rui-Zhi RZ Zhou Ying-Xia YX He Chao C Yang Xin X

Cell death discovery 20220519 1

Hepatic fibrosis (HF) is caused by chronic hepatic injury and is characterized by hepatic stellate cells (HSCs) activation. Studies focusing on the function of exosomes derived from macrophages in HF progression are limited. This study aims to identify the roles of exosomal NEAT1 derived from macrophages on HF and the underlying mechanisms. Our studies showed that METTL3 targeted and enhanced NEAT1 expression in macrophages. Exosomal NEAT1 originating from LPS-treated macrophages promoted HSCs p ...[more]

PMID: 35585044

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Project description:BackgroundIn mice, liver fibrosis is the most serious pathologic change during Schistosoma japonicum (S. japonicum) infection. Schistosomiasis is mainly characterized by schistosome egg-induced granulomatous fibrosis. Hepatic stellate cells (HSCs) are mainly responsible for the net accumulation of collagens and fibrosis formation in the liver. Activated HSCs regulated by transforming growth factor-β1 (TGF-β1)/Smad signaling have emerged as the critical regulatory pathway in hepatitis virus or carbon tetrachloride-induced liver fibrosis. However, the detailed mechanism of HSC activation in schistosome-induced liver fibrosis is poorly understood.MethodsSchistosoma japonicum-induced murine models and a control group were generated by abdominal infection with 15 (± 1) cercariae. The purity of cultured primary HSCs was evaluated by immunocytochemistry. The histopathological changes in the livers of infected mice were estimated by hematoxylin-eosin and Masson staining. Dynamic expression of pro-fibrotic molecules and microRNAs was detected by real-time quantitative PCR (RT-qPCR). Mainly members involved in the TGF-β1/Smad signaling pathway were examined via RT-qPCR and Western blot.ResultsThe egg-induced granulomatous inflammation formed at 4 weeks post-infection (wpi) and developed progressively. Alpha-smooth muscle actin (α-SMA), collagen I, collagen III, TGF-β1, Smad2, Smad3, and Smad4 showed a significant increase in mitochondrial RNA (mRNA) and protein expression compared with the control group at 7 and 9 weeks post-infection (wpi), while an opposite effect on Smad7 was observed. In addition, the mRNA expression of microRNA-21 (miRNA-21) was significantly increased at 7 wpi, and the mRNA expression of miRNA-454 was decreased starting from 4 wpi.ConclusionOur present findings revealed that HSCs regulated by the TGF-β1/Smad signaling pathway play an important role in liver fibrosis in S. japonicum-infected mice, which may provide proof of concept for liver fibrosis in schistosomiasis.

Project description:ObjectivesLiver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer.Materials and methodsThe effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl4)-induced rat liver fibrosis model. In vitro, HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored.ResultsAKF-PD attenuated liver injury and ECM deposition in the CCl4-induced liver fibrosis model. In vitro, the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer.ConclusionsAKF-PD alleviates liver fibrosis by inhibiting HSC autophagy via the transforming growth factor (TGF)-β1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.

Dataset Information

METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway.

Publications

METTL3-mediated macrophage exosomal NEAT1 contributes to hepatic fibrosis progression through Sp1/TGF-β1/Smad signaling pathway.

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