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TGF? inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

ABSTRACT: Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional signature associated with the induction of paracrine senescence was observed within 24 hours and was followed by one of impaired proliferation. In mouse genetic models of hepatocyte injury and senescence, we observed transmission of senescence to local uninjured hepatocytes. Spread of senescence depended on macrophage-derived transforming growth factor-?1 (TGF?1) ligand. In acetaminophen poisoning, inhibition of TGF? receptor 1 (TGF?R1) improved mouse survival. TGF?R1 inhibition reduced senescence and enhanced liver regeneration even when delivered beyond the therapeutic window for treating acetaminophen poisoning. This mechanism, in which injury-induced senescence impairs liver regeneration, is an attractive therapeutic target for developing treatments for acute liver failure.

SUBMITTER: Bird TG

PROVIDER: S-EPMC6420144 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

Bird Thomas G TG Müller Miryam M Boulter Luke L Vincent David F DF Ridgway Rachel A RA Lopez-Guadamillas Elena E Lu Wei-Yu WY Jamieson Thomas T Govaere Olivier O Campbell Andrew D AD Ferreira-Gonzalez Sofía S Cole Alicia M AM Hay Trevor T Simpson Kenneth J KJ Clark William W Hedley Ann A Clarke Mairi M Gentaz Pauline P Nixon Colin C Bryce Steven S Kiourtis Christos C Sprangers Joep J Nibbs Robert J B RJB Van Rooijen Nico N Bartholin Laurent L McGreal Steven R SR Apte Udayan U Barry Simon T ST Iredale John P JP Clarke Alan R AR Serrano Manuel M Roskams Tania A TA Sansom Owen J OJ Forbes Stuart J SJ

Science translational medicine 20180801 454

Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure. In human acute liver disease, and murine models, p21-dependent hepatocellular senescence was proportionate to disease severity and was associated with impaired regeneration. In an acetaminophen injury mouse model, a transcriptional si ...[more]

PMID: 30111642

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Project description:ObjectiveIn this study, we mainly explored the mechanism and target of the anti-inflammatory effects of Aureusidin (Aur) in acute liver injury.MethodsLipopolysaccharide (LPS) was used to induce inflammatory injury in Kupffer cells (KCs) in vitro. After Aur treatment with gradient concentration, flow cytometry, propidium iodide (PI) staining, and Hoechst 33342 staining were used to detect the apoptotic level of KCs, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the expression levels of inflammatory factors, including Interleukin-1β (IL-1β), Interleukin-18 (IL-18), and tumor necrosis factor alpha (TNF-α). Western blot was used to detect the expression of toll-like receptor 4 (TLR4), myeloid differentiation protein-2 (MD2), MyD88, and p-P65. Aur was labeled with biotin, followed by a pull-down assay to detect its binding with MD2. Moreover, D-GalN/LPS was used to induce acute liver injury in mice in vitro, followed by Aur treatment by gavage. H&E staining was used to detect the pathological changes of liver tissue, an IF assay was used to detect the expression of MD2, Western blot was used to detect the expression of relevant proteins.ResultsAur pretreatment could significantly inhibit LPS-induced KC injury, downregulate the apoptotic level, inhibit the expression of inflammatory factors, decrease the level of MDA, and downregulate the expression of MD2 in cells. Aur could inhibit the activation level of TLR4/MD2-NF-κB in a dose-dependent pattern, a high dose of Aur had a superior effect compared to low-dose Aur. In the case of MD2 deletion, the effects of Aur were suppressed. Additionally, pull-down and co-immunoprecipitation assays show that Aur can bind with the MD2 protein to inhibit the activation of TLR4/MD2-NF-κB. Results of mice experiments also showed that Aur could relieve liver injury, decrease the levels of ALT and AST, and simultaneously downregulate the levels of inflammatory factors in tissues and peripheral blood.ConclusionWe found that Aur exerted an anti-inflammatory effect by directly targeting the MD2 protein, further inhibiting the expression of TLR4/MD2-NF-κB, thereby relieving acute liver injury. Therefore, Aur might be a potential inhibitor for MD2.

Dataset Information

TGF? inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

Publications

TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence.

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