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Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo , we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism. Tumour cells can survive by evading cell death pathways and altering their metabolism to adapt to their local environment. In this study, Iansante et al . show that the anti-apoptotic protein PARP14 maintains low PKM2 activity, leading to enhanced glycolysis, demonstrating a link between suppression of apoptosis and altered metabolism.

Mutations in IDH1/2 and the epigenetic silencing of TET2 occur in leukaemia or glioma in a mutually exclusive manner. Although intrahepatic cholangiocarcinoma (iCCA) may harbour IDH1/2 mutations, the contribution of TET2 to carcinogenesis remains unknown. In the present study, the expression and promoter methylation of TET2 were investigated in iCCA. The expression of TET2 was assessed in 52 cases of iCCA (small-duct type, n = 33; large-duct type, n = 19) by quantitative PCR, immunohistochemistry (IHC) and a sequencing-based methylation assay, and its relationships with clinicopathological features and alterations in cancer-related genes (e.g., KRAS and IDH1) were investigated. In contrast to non-neoplastic bile ducts, which were negative for TET2 on IHC, 42 cases (81%) of iCCA showed the nuclear overexpression of TET2. Based on IHC scores (area × intensity), these cases were classified as TET2-high (n = 25) and TET2-low (n = 27). The histological type, tumour size, lymph node metastasis and frequency of mutations in cancer-related genes did not significantly differ between the two groups. Overall and recurrence-free survival were significantly worse in patients with TET2-high iCCA than in those with TET2-low iCCA. A multivariate analysis identified the high expression of TET2 as an independent prognostic factor (HR = 2.94; p = 0.007). The degree of methylation at two promoter CpG sites was significantly less in TET2-high iCCA than in TET2-low iCCA or non-cancer tissue. In conclusion, in contrast to other IDH-related neoplasms, TET2 overexpression is common in iCCA of both subtypes, and its high expression, potentially induced by promoter hypomethylation, is an independent poor prognostic factor.

Transposable elements (TEs) make up around half of the human genome. Their transcription is repressed in most somatic cells to maintain genome integrity and function. The repression is chiefly maintained by a combination of epigenetic modifications such as DNA methylation and histone modifications. However, recent research suggests that liver steatosis is associated with extensive changes to the hepatocyte epigenome. Furthermore, studies in mice have reported diet- and drug-induced changes to TE transcript levels in liver. The confirmation of these effects in human liver has not previously been undertaken. Here, we examined TE transcription in liver tissue from three patient cohorts with histologically confirmed liver steatosis caused by alcohol consumption or metabolic dysfunction. The quantitation of the number of transcripts with TE-homology in RNA-Seq data from a cohort of 90 bariatric surgery patients with metabolic dysfunction-associated steatotic liver disease (MASLD) revealed a trend for the reduction in TEs of all classes due to increasing steatosis, but no effect of fibrosis. This pattern was also present in a separate cohort of MASLD and HCC patients, as RT-qPCR also showed a reduction in Alu element transcripts in advanced steatosis, but again, no effect of fibrosis. Contrastingly, in a cohort of alcohol-related liver disease patients, the reduction in LINE-1 transcripts was associated with either increased steatosis or increased fibrosis. Moreover, the examination of LINE-1 DNA methylation levels in the MASLD and HCC cohort indicated that DNA methylation was also negatively associated with LINE-1 transcription in MASLD. This study suggests that TE transcript levels in human liver are slightly reduced by steatosis, that DNA methylation is an influential epigenetic regulator of LINE-1 retrotransposon transcription in steatosis, and that Alu transcript levels in background liver could be a new biomarker for HCC in cirrhotic and non-cirrhotic MASLD.

Background The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Methods Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. Results Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. Conclusions Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.

BACKGROUND:Intestinal dysbiosis with gut barrier impairment (GBI) and bacterial translocation (BT) are recognised as central features of acutely decompensated cirrhosis (AD) and propagating hepatic encephalopathy (HE). Gut mucosal function is technically challenging to investigate, with a difficulty in obtaining representative tissue in cirrhotics and a paucity of non-invasive techniques. A novel assay we developed was to quantify faecal cytokines (FC) as surrogate makers of intestinal inflammation, compared to GBI markers and systemic cytokines.METHODS:Protein was extracted from faeces of patients with stable cirrhosis (SC; n = 16), AD (n = 48), and healthy participants (HC; n = 31). A multiplex panel of 13 cytokines were quantified by electrochemiluminescence or ELISA in paired faecal lysates and plasma. Intestinal epithelium-associated fatty acid binding protein 2 (FABP2) and intestinal-microbiota metabolite D-lactate, as markers of intestinal barrier disruption, were quantified by ELISA and colorimetric enzymatic assay, respectively.RESULTS:Median ages and MELD scores of AD vs SC patients were 61 (53–68) vs 55 (44–59) years and 18 (13–26) vs 8 (7.0–8.5), respectively. Male gender predominated (AD: 65%; SC: 75%) The causes of cirrhosis were alcohol, NAFLD and treated hepatitis C. Median venous ammonia levels were significantly higher in AD vs SC (51 [38–74] vs 36 [26–59], P = 0.027). Faecal IL-1β, IFN-γ, TNF-α, IL-21, IL-17A/F and IL-22 were significantly different in AD vs SC on univariate comparison (q < 0.01 all comparisons). Along with IL-1β, faecal IL-23 was significantly elevated in AD vs HC (P = 0.0007), important in promoting deleterious Th17 cell effector function. Faecal FABP2 and D-lactate (P < 0.0001 for both) and plasma FABP2 and D-lactate (P = 0.0004; P = 0.011) were significantly elevated in AD vs SC and AD vs HC, respectively, consistent with GBI. FABP2 was the faecal marker that correlated most strongly with disease scores (Spearman's rho: Child-Pugh 0.466, P < 0.0001; MELD 0.488, P < 0.0001). With the exception of IL-8, IL-12 & IL-23, faecal cytokines and D-lactate were more discriminant than circulating equivalent molecules in discriminating AD from SC by Principal Component Analysis (Figure 1).CONCLUSIONS:FC profiling represents a novel targeted approach to localised measurement of the intestinal cytokine milieu in cirrhosis, and in conjunction with D-lactate, demonstrates that progression to AD from SC may be a intestinally initiated and mediated process. The AD gut micro-environment may skew T cell priming away from restorative Tregs and towards inflammatory Th1/Th17 profiles, promoting epithelial barrier damage and preventing repair. These data provide insights into intestinal mucosal injury and GBI, as a novel pathobiology in AD and HE.

IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses . We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4 T cells producing IFN-γ with maintenance of HBV-specific CD8 T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8 T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment. ClinicalTrials.gov NCT01204762.

Now, much is known regarding the impact of chronic and heavy alcohol consumption on the disruption of physiological liver functions and the induction of structural distortions in the hepatic tissues in alcohol-associated liver disease (ALD). This review deliberates the effects of alcohol on the activity and properties of liver non-parenchymal cells (NPCs), which are either residential or infiltrated into the liver from the general circulation. NPCs play a pivotal role in the regulation of organ inflammation and fibrosis, both in the context of hepatotropic infections and in non-infectious settings. Here, we overview how NPC functions in ALD are regulated by second hits, such as gender and the exposure to bacterial or viral infections. As an example of the virus-mediated trigger of liver injury, we focused on HIV infections potentiated by alcohol exposure, since this combination was only limitedly studied in relation to the role of hepatic stellate cells (HSCs) in the development of liver fibrosis. The review specifically focusses on liver macrophages, HSC, and T-lymphocytes and their regulation of ALD pathogenesis and outcomes. It also illustrates the activation of NPCs by the engulfment of apoptotic bodies, a frequent event observed when hepatocytes are exposed to ethanol metabolites and infections. As an example of such a double-hit-induced apoptotic hepatocyte death, we deliberate on the hepatotoxic accumulation of HIV proteins, which in combination with ethanol metabolites, causes intensive hepatic cell death and pro-fibrotic activation of HSCs engulfing these HIV- and malondialdehyde-expressing apoptotic hepatocytes.

Alcohol-associated liver disease (ALD) is a substantial cause of morbidity and mortality worldwide and represents a spectrum of liver injury beginning with hepatic steatosis (fatty liver) progressing to inflammation and culminating in cirrhosis. Multiple factors contribute to ALD progression and disease severity. Here, we overview several crucial mechanisms related to ALD end-stage outcome development, such as epigenetic changes, cell death, hemolysis, hepatic stellate cells activation, and hepatic fatty acid binding protein 4. Additionally, in this review, we also present two clinically relevant models using human precision-cut liver slices and hepatic organoids to examine ALD pathogenesis and progression.

Alcoholic liver disease (ALD) is an escalating global problem accounting for more than 3 million deaths annually. Bacterial infections are diagnosed in 25–47% of hospitalized patients with cirrhosis and represent the most important trigger for acute decompensation, multi-organ failure, septic shock and death. Current guidelines recommend intensive antibiotic therapy, but this has led to the emergence of multi-drug resistant bacteria, which are associated with increased morbidity and mortality rates. As such, there is a pressing need to explore new paradigms for anti-infective therapy and host-directed immunomodulatory therapies are a promising approach. Paradoxically, cirrhotic patients are characterised by heightened immune activity and exacerbated inflammatory processes but are unable to contend with bacterial infection, demonstrating that whilst immune effector cells are primed, their antibacterial effector functions are switched-off, reflecting a skewed homeostatic balance between anti-pathogen immunity and host-induced immunopathology. Preservation of this equilibrium physiologically is maintained by multiple immune-regulatory checkpoints and these feedback receptors serve as pivotal regulators of the host immunity. Checkpoint receptor blockade is proving to be effective at rescuing deranged/exhausted immunity in pre-clinical studies for chronic viral infection and sepsis. This approach has also obtained FDA approval for restoring anti-tumor immunity, with improved response rates and good safety profiles. To date, no clinical studies have investigated checkpoint blockade in ALD, highlighting an area for development of host-targeted immunotherapeutic strategies in ALD, for which there are no current specific treatment options. This review aims at framing current knowledge on immune checkpoints and the possibility of their therapeutic utility in ALD-associated immune dysfunctions.