MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis.

Background & Aim: MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis.

Biodistribution and function of extracellular miRNA-155 in mice.

Circulating miRNAs can be found in extracellular vesicles (EV) and could be involved in intercellular communication. Here, we report the biodistribution of EV associated miR-155 using miR-155 KO mouse model. Administration of exosomes loaded with synthetic miR-155 mimic into miR-155 KO mice resulted in a rapid accumulation and clearance of miR-155 in the plasma with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively).

Converging actions of alcohol on liver and brain immune signaling.

Chronic excessive alcohol consumption results in inflammation in multiple organs, including the brain. While the contribution of neuroinflammation to alcohol-related cognitive dysfunction and behavioral alterations is established, the mechanisms by which alcohol triggers inflammation in the brain are only partially understood. There are acute and long-term alterations in brain function due to intercellular and intracellular changes of different cell types as a result of alcohol consumption.

Micro-RNA-155 deficiency prevents alcohol-induced serum endotoxin increase and small bowel inflammation in mice.

Background: Chronic alcohol impairs gut barrier function and induces inflammatory cytokines. The effects of acute alcohol binge on the gut are partially understood. Micro-RNA-155 (miR-155), a modulator of cytokine and T-cell immune response in the gut, stabilizes tumor necrosis factor-α (TNFα) mRNA.

microRNA-122 regulates hypoxia-inducible factor-1 and vimentin in hepatocytes and correlates with fibrosis in diet-induced steatohepatitis.

Background & Aims: miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1α (HIF-1α). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis.

Both bone marrow-derived and non-bone marrow-derived cells contribute to AIM2 and NLRP3 inflammasome activation in a MyD88-dependent manner in dietary steatohepatitis.

Background & Aims: Inflammation promotes the progression of non-alcoholic steatohepatitis (NASH). Toll-like receptor 4 (TLR4) and TLR9 activation through myeloid differentiation primary response gene 88 (MyD88) and production of mature interleukin-1β (IL-1β) via inflammasome activation contribute to steatohepatitis. Here, we investigated the inter-relationship between TLR signalling and inflammasome activation in dietary steatohepatitis.

Chronic alcohol-induced microRNA-155 contributes to neuroinflammation in a TLR4-dependent manner in mice.

Introduction: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-α (TNFα), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1β). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-κB (NF-κB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process.

Alcohol-induced IL-1β in the brain is mediated by NLRP3/ASC inflammasome activation that amplifies neuroinflammation.

Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1β. IL-1β production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1β in the brain.

IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice.

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1).

Molecular hepatic carcinogenesis: impact of inflammation.

Hepatocellular cancer (HCC) represents one of the most rapidly spreading cancers in the world. Most HCC develops in cirrhotic livers after prolonged inflammation, supporting the hypothesis that inflammation contributes to cancer development. Increasing evidence suggests that inflammatory cell recruitment and activation is an important contributor to promoting cancerous malformation in hepatocytes.

Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice.

Unlabelled: Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA).

Deficiency in myeloid differentiation factor-2 and toll-like receptor 4 expression attenuates nonalcoholic steatohepatitis and fibrosis in mice.

Toll-like receptor 4 (TLR4) and its coreceptor, myeloid differentiation factor-2 (MD-2), are key in recognition of lipopolysaccharide (LPS) and activation of proinflammatory pathways. Here we tested the hypothesis that TLR4 and its coreceptor MD-2 play a central role in nonalcoholic steatohepatitis (NASH) and liver fibrosis in nonalcoholic fatty liver disease. Mice of control genotypes and those deficient in MD-2 or TLR4 [knockout (KO)] received methionine choline-deficient (MCD) or methionine choline-supplemented (MCS) diet.

[Eosinophilic esophagitis].

Eosinophilic esophagitis (EE) is a chronic esophageal inflammatory disease mediated by oral antigens with the infiltration of eosinophilic granulocytes. EE can lead to various reflux-like symptoms including dysphagia, progressive strictures and bolus obstruction. EE mostly affects young male population and is associated with atopic disorders and sensitization to oral antigens.