Dataset Information

CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.

ABSTRACT:

Background

Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis.

Methods

CD5L was measured by ELISA in plasma samples from cirrhotic (n?=?63) and hepatitis (n?=?39) patients, and healthy controls (n?=?7), by immunohistochemistry in cirrhotic tissue (n?=?12), and by quantitative RT-PCR in mouse liver cell subsets isolated by cell sorting. Recombinant CD5L (rCD5L) was administered into a murine model of CCl₄-induced fibrosis, and damage, fibrosis and hepatic immune cell infiltration, including the LyC6^hi (pro-fibrotic)-LyC6^low (pro-resolutive) monocyte ratio were determined. Moreover, rCD5L was added into primary human hepatic stellate cells to study transforming growth factor ? (TGF?) activation responses.

Findings

Cirrhotic patients showed elevated plasma CD5L concentrations as compared to patients with hepatitis and healthy controls (Mann-Whitney test p?4-induced damage increased CD5L levels in total liver, particularly in hepatocytes and macrophages. rCD5L administration attenuated CCl₄-induced injury and fibrosis as determined by reduced serum transaminase and collagen content. Moreover, rCD5L inhibited immune cell infiltration and promoted a phenotypic shift in monocytes from LyC6^hi to LyC6^low. Interestingly, rCD5L also had a direct effect on primary human hepatic stellate cells promoting SMAD7 expression, thus repressing TGF? signalling.

Interpretation

Our study identifies CD5L as a key pleiotropic inhibitor of chronic liver injury. FUND: Fundació Marató TV3, AGAUR and the ISCIII-EDRF.

SUBMITTER: Barcena C

PROVIDER: S-EPMC6558273 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.

Bárcena Cristina C Aran Gemma G Perea Luís L Sanjurjo Lucía L Téllez Érica É Oncins Anna A Masnou Helena H Serra Isabel I García-Gallo Mónica M Kremer Leonor L Sala Margarita M Armengol Carolina C Sancho-Bru Pau P Sarrias Maria-Rosa MR

EBioMedicine 20190508

<h4>Background</h4>Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis.<h4>Methods</h4>CD5L was measured by ELISA in plasma samples from cirrhotic (n = 63) and hepatitis (n = 39) patients, and healthy controls (n = 7), by immunohistochemistry in cirrhotic tissue (n = 12), and by quantitative RT-PCR in mouse liver cell subsets isolated ...[more]

PMID: 31076347

Similar Datasets

Project description:Background & aimsFibrosis, the primary cause of morbidity in chronic liver disease, is induced by pro-inflammatory cytokines, immune cell infiltrates, and tissue resident cells that drive excessive myofibroblast activation, collagen production, and tissue scarring. Rho-associated kinase 2 (ROCK2) regulates key pro-fibrotic pathways involved in both inflammatory reactions and altered extracellular matrix remodelling, implicating this pathway as a potential therapeutic target.MethodsWe used the thioacetamide-induced liver fibrosis model to examine the efficacy of administration of the selective ROCK2 inhibitor KD025 to prevent or treat liver fibrosis and its impact on immune composition and function.ResultsProphylactic and therapeutic administration of KD025 effectively attenuated thioacetamide-induced liver fibrosis and promoted fibrotic regression. KD025 treatment inhibited liver macrophage tumour necrosis factor production and disrupted the macrophage niche within fibrotic septae. ROCK2 targeting in vitro directly regulated macrophage function through disruption of signal transducer and activator of transcription 3 (STAT3)/cofilin signalling pathways leading to the inhibition of pro-inflammatory cytokine production and macrophage migration. In vivo, KDO25 administration significantly reduced STAT3 phosphorylation and cofilin levels in the liver. Additionally, livers exhibited robust downregulation of immune cell infiltrates and diminished levels of retinoic acid receptor-related orphan receptor gamma (RORγt) and B-cell lymphoma 6 (Bcl6) transcription factors that correlated with a significant reduction in liver IL-17, splenic germinal centre numbers and serum IgG.ConclusionsAs IL-17 and IgG-Fc binding promote pathogenic macrophage differentiation, together our data demonstrate that ROCK2 inhibition prevents and reverses liver fibrosis through direct and indirect effects on macrophage function and highlight the therapeutic potential of ROCK2 inhibition in liver fibrosis.Lay summaryBy using a clinic-ready small-molecule inhibitor, we demonstrate that selective ROCK2 inhibition prevents and reverses hepatic fibrosis through its pleiotropic effects on pro-inflammatory immune cell function. We show that ROCK2 mediates increased IL-17 production, antibody production, and macrophage dysregulation, which together drive fibrogenesis in a model of chemical-induced liver fibrosis. Therefore, in this study, we not only highlight the therapeutic potential of ROCK2 targeting in chronic liver disease but also provide previously undocumented insights into our understanding of cellular and molecular pathways driving the liver fibrosis pathology.

Project description:Schistosomiasis is a widespread helminth disease that poses a heavy social and economic burden on people worldwide. Advanced schistosomiasis often develops into schistosome-associated liver fibrosis, the pathogenesis of which remains unclear. This study aimed preliminarily to profile immune cells of schistosome-associated liver fibrosis using single-cell RNA sequencing. Three patient groups were enrolled, including an Schistosomiasis japonicum (SJ) group (n = 1), a chronic liver failure (CLF) group (n = 3) and a healthy control (HC) group (n = 2), revealing 17 cell clusters out of 20 093 cells. From these limited datasets, it was observed that T cell(1), mononuclear phagocytes-1 and dendritic cells (DCs) were higher in the SJ group. CAVIN2+ MP(2) was the predominant cell type in the MP subset of the SJ group (53%), and was higher than that in both the CLF (8%) and HC (1%) groups. Kupffer cell marker genes (CD163, MARCO and TIMD4) were enriched in caveolae-associated protein 2 (CAVIN2)+ MP(2), which was also an important source of TGFB1. The KEGG pathways of CAVIN2+ MP(2) indicated that they were associated with lysosome, endocytosis, phagosome and antigen processing and presentation. The preliminary study showed that granzyme B (GZMB)+ T cell(1) and ankyrin repeat domain-containing protein 36B+ T cell(3) were the most common T cells in the SJ group (50% and 32%, respectively). The KEGG pathways of GZMB+ T cell(1) were mainly related to natural killer cell-mediated cytotoxicity. The percentage of ring1 and YY1 binding protein (RYBP)+ DC(1) was higher in the SJ group (57%) than in the CLF (16%) and HC (6%) groups. The KEGG pathway of RYBP+ DC(1) was related to Fc gamma R-mediated phagocytosis and antigen processing and presentation. Overall, CAVIN2+ Kupffer cells were the main source of TGFB1, consisting primarily of mononuclear phagocytes in the livers of the SJ group subjects and potentially playing an irreplaceable role in hepatic fibrosis of schistosomiasis.

Project description:Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

Project description:IntroductionHepatic stellate cells (HSC) become activated, differentiate to myofibroblasts and produce extracellular fibrillar matrix during liver fibrosis. The hepatic fibrogenic response is orchestrated by reciprocal interactions between HSCs and macrophages and their secreted products. SOCS1 can regulate several cytokines and growth factors implicated in liver fibrosis. Here we investigated the role of SOCS1 in regulating HSC activation.MethodsMice lacking SOCS1 in HSCs (Socs1ΔHSC) were generated by crossing Socs1fl/fl and LratCre mice. Liver fibrosis was induced by carbon tetrachloride and evaluated by Sirius red staining, hydroxyproline content and immunostaining of myofibroblasts. Gene expression of pro-fibrogenic factors, cytokines, growth factors and chemokines were quantified by RT-qPCR. The phenotype and the numbers of intrahepatic leukocyte subsets were studied by flow cytometry. The impact of fibrosis on the development of diethyl nitrosamine-induced hepatocellular carcinoma was evaluated.ResultsSocs1ΔHSC mice developed more severe liver fibrosis than control Socs1fl/fl mice that was characterized by increased collagen deposition and myofibroblast differentiation. Socs1ΔHSC mice showed a significant increase in the expression of smooth muscle actin, collagens, matrix metalloproteases, cytokines, growth factors and chemokines in the liver following fibrosis induction. The fibrotic livers of Socs1ΔHSC mice displayed heightened inflammatory cell infiltration with increased proportion and numbers of Ly6ChiCCR2+ pro-inflammatory macrophages. This macrophage population contained elevated numbers of CCR2+CX3CR1+ cells, suggesting impaired transition towards restorative macrophages. Fibrosis induction following exposure to diethyl nitrosamine resulted in more numerous and larger liver tumor nodules in Socs1ΔHSC mice than in Socs1fl/fl mice.DiscussionOur findings indicate that (i) SOCS1 expression in HSCs is a critical to control liver fibrosis and development of hepatocaellular carcinoma, and (ii) attenuation of HSC activation by SOCS1 regulates pro-inflammatory macrophage recruitment and differentiation during liver fibrosis.

Dataset Information

CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.

Background

Methods

Findings

Interpretation

Publications

CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets