Dataset Information

Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.

ABSTRACT: Although hepatic fibrosis typically follows chronic inflammation, fibrosis will often regress after cessation of liver injury. In this study, we examined whether liver dendritic cells (DCs) play a role in liver fibrosis regression using carbon tetrachloride to induce liver injury. We examined DC dynamics during fibrosis regression and their capacity to modulate liver fibrosis regression upon cessation of injury. We show that conditional DC depletion soon after discontinuation of the liver insult leads to delayed fibrosis regression and reduced clearance of activated hepatic stellate cells, the key fibrogenic cell in the liver. Conversely, DC expansion induced either by Flt3L (fms-like tyrosine kinase-3 ligand) or adoptive transfer of purified DCs accelerates liver fibrosis regression. DC modulation of fibrosis was partially dependent on matrix metalloproteinase (MMP)-9, because MMP-9 inhibition abolished the Flt3L-mediated effect and the ability of transferred DCs to accelerate fibrosis regression. In contrast, transfer of DCs from MMP-9-deficient mice failed to improve fibrosis regression.Taken together, these results suggest that DCs increase fibrosis regression and that the effect is correlated with their production of MMP-9. The results also suggest that Flt3L treatment during fibrosis resolution merits evaluation to accelerate regression of advanced liver fibrosis.

SUBMITTER: Jiao J

PROVIDER: S-EPMC3245345 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.

Jiao Jingjing J Sastre David D Fiel Maria Isabel MI Lee Ursula E UE Ghiassi-Nejad Zahra Z Ginhoux Florent F Vivier Eric E Friedman Scott L SL Merad Miriam M Aloman Costica C

Hepatology (Baltimore, Md.) 20120101 1

<h4>Unlabelled</h4>Although hepatic fibrosis typically follows chronic inflammation, fibrosis will often regress after cessation of liver injury. In this study, we examined whether liver dendritic cells (DCs) play a role in liver fibrosis regression using carbon tetrachloride to induce liver injury. We examined DC dynamics during fibrosis regression and their capacity to modulate liver fibrosis regression upon cessation of injury. We show that conditional DC depletion soon after discontinuation ...[more]

PMID: 21898476

Similar Datasets

Project description:Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.

Project description:Abstract from Knabel et al. PLoS One (2015): Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include mir29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of mir-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders. The Taqman MicroRNA Array (Taqman Array Rodent MicroRNA A Cards v2.0, ABI) was run, using manufacturer's protocols, on 3 groups of mice with varying amounts fibrotic injury. The groups include carbon tetrachloride intraperitinially injected bi-weekly for 1, 4, and 8 weeks with n=4, 3, and 2 respectively for each group. The RNA was isolated from whole liver using the MiRvana miRNA Isolation Kit (Ambion) according to manufacturer's protocols. The fold_change.txt contains the following data columns; ID_Ref: mmu-miR being quantified not-treated (FC): Fold Change compared to not-treated group using Geometric mean normalization 1 week (FC): Fold Change compared to not-treated group using Geometric mean normalization 4 weeks (FC): Fold Change compared to not-treated group using Geometric mean normalization 8 weeks (FC): Fold Change compared to not-treated group using Geometric mean normalization

Dataset Information

Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.

Publications

Dendritic cell regulation of carbon tetrachloride-induced murine liver fibrosis regression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets