Editorial: Cell-to-cell communications in alcohol-associated, metabolic-related and viral liver diseases

Le résumé fourni par la source

There were three reviews that described the pathogenic mechanism of liver disease progression with a focus on cell-to-cell communication. A review by Osna covers some important new aspects of the alcohol-induced communications between liver parenchymal and non-parenchymal cells. The review disclosed major mechanisms of cell-to-cell communications pertaining to alcoholinduced liver injury progression. In particular, the authors discussed how the information is exchanged between various cell types through multiple mechanisms, such as direct cell-to-cell interactions, extracellular vesicles (EVs) or chemokines, cytokines, and growth factors contained in extracellular fluids/cell culture supernatants to promote end-stage liver disease progression. In particular, the authors highlighted the role of EVs derived from alcohol-exposed hepatocytes (HCs) in the activation of non-parenchymal cells, liver macrophages (LM), and hepatic stellate cells (HSC). The authors further expounded on EV-mediated crosstalk between liver parenchymal and non-parenchymal cells in the settings of HIV and alcohol co-exposure. In addition, the literature on the crosstalk between cell death pathways and inflammasome activation in alcoholactivated HCs and macrophages was presented. Furthermore, they cover highly clinically relevant studies on the role of non-inflammatory factors, sinusoidal pressure, and hepatic arterialization in alcohol-induced hepatic fibrogenesis. In conclusion the authors identify therapeutically important targets, which can be used for alcohol-associated liver disease (ALD) prevention.Another review by Machida focused on the tumor-initiating stem-like cells (TIC) population, which are the prime origin of cancer recurrence in drug-treated patients with hepatocellular carcinoma (HCC). This informative review is very timely because while the incidence of many cancer types has trended downward, that is not the case for HCC. Therefore, understanding the mechanism of HCC development and therapy resistance is important to combat this deadly disease which has limited treatment options with a dismal 3 year-survival rate of 13-21% without any curative treatment. In this review, the author illustrates the multiple hits by hepatitis C virus (HCV) that eventually promotes transformation and TIC genesis that leads to HCC development. This review article describes the links between HCV-associated HCC and TICs with discussions on 1) how HCV promotes the genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hallmarks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.Another review article by Huang explore the role of mast cells in the progression of liver disease. In this review article the authors focused on mast cells and their mediators that can regulate liver disease. It is known that upon activation, mast cells degranulate and release many mediators, such as histamine, tryptase, chymase, transforming growth factor-β1, tumor necrosis factor-α, interleukins cytokines, and other substances. These substances are also known to mediate the progression of liver disease. Thus, while the role of mast cells is well known in association with allergic diseases, parasites, bacteria, and venoms, this article reviews the role of mast cells and their secretory mediators in developing hepatitis, cirrhosis and HCC and their essential role in immunotherapy. The authors conclude that targeting mast cell infiltration may be a novel therapeutic option for improving liver disease progression of diverse etiologies.An original article by Garcia revealed that liver steatosis (fat accumulation), irrespective of etiology, causes impaired clearance of amyloid-beta (Aβ) resulting in its accumulation in the brain promoting the development of Alzheimer's disease (AD). Since heavy alcohol consumption is a known risk factor for AD, the authors first investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. The authors report that four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in Aβ processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver that removes Aβ from blood and peripheral organs, and 2) alcohol significantly upregulated APP (∼2-fold), a potentially important source of Aβ in the periphery and brain. The decrease in hepatic LRP1 and increase in hepatic APP likely switches the liver from being a remover or low producer of Aβ to an important source of Aβ in the periphery, which can impact the brain. The downregulation of LRP1 and upregulation of APP in the liver was observed in the first week of intragastric alcohol feeding and occurred in other alcohol feeding models (NIAAA binge alcohol model and intragastric alcohol feeding to rats). Modulation of hepatic LRP1 and APP does not seem alcohol-specific, as ob/ob mice (mutant mice that are hyperphagic because of mutation in gene responsible for leptin production and hence are obese with significant steatosis) also had decline in LRP1 and increases in APP expression in the liver. These findings suggest that liver steatosis rather than alcohol-induced liver injury is likely responsible for the regulation of hepatic LRP1 and APP. Since both obesity and alcohol intake have been linked to AD, the authors conclude that liver steatosis associated with these two conditions modulates hepatic LRP1 and APP to disrupt liver Aβ processing to promote AD.Overall, this Topical collection covers important aspects on the molecular mechanism(s) that mediate the development and progression of alcohol-associated, metabolically-related, and viral liver disease for better understanding of the disease, and potential new biomarkers / therapeutic targets. The published articles are recommended for scientists and physicians involved in basic, translational and/or clinical studies on ALD. We strongly feel that the efforts of the guest editors and the journal in developing this Topical issue will be a small but significant step towards understanding, awareness, and hopefully reducing the disease burden.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.