Extracellular vesicles in inflammation: Focus on the microRNA cargo of EVs in modulation of liver diseases

Abstract

Extracellular vesicles (EVs) are heterogeneous nanometer‐ranged particles that are released by cells under both normal and pathological conditions. EV cargo comprises of DNA, protein, lipids cargo, metabolites, mRNA, and non‐coding RNA that can modulate the immune system by altering inflammatory response. EV associated miRNAs contribute to the pathobiology of alcoholic liver disease, non‐alcoholic liver disease, viral hepatitis, acetaminophen‐induced liver injury, fibrosis, and hepatocellular carcinoma. In context of liver diseases, EVs, via their cargo, alter the inflammatory response by communicating with different cell types within the liver and between liver and other organs. Here, the role of EVs and its associated miRNA in inter‐cellular communication in different liver disease and as a potential biomarker and therapeutic target is reviewed.

Pathogenesis of Alcohol-Associated Liver Disease

“…297 Overall, EVs are becoming valuable tools for detecting cell-to-cell and interorgan communication after alcohol exposure. 298 With further characterization, they will likely serve as essential diagnostic tools to characterize the varying pathologies that characterize the advancing stages in the spectrum of ALD. The scheme of EV-based interactions crucial for ALD development is presented in Figure 6.…”

Alcohol Promotes Exosome Biogenesis and Release via Modulating Rabs and miR-192 Expression in Human Hepatocytes

“…Total number of particles was evaluated from the cell free supernatant after miR-192 inhibition using Nanosight and presented as particles/ml (L). Heravi et al, 2015b;Hessvik and Llorente, 2018;Babuta et al, 2019;Babuta and Szabo, 2021). Majority of alcohol is metabolized in hepatocytes and alcohol metabolites induce oxidative stress (Momen-Heravi et al, 2015a).…”

“…There are several factors such as RNA binding proteins (Ago2, hnRNPs and others), cellular stress, membrane proteins (such as neural sphingomyelinase 2) and the miRNA induced silencing complex (miRISC)-related pathway that affect the sorting of miRNA/cargoes into exosomes (Zhang et al, 2015;Fabbiano et al, 2020;Groot and Lee, 2020;Babuta and Szabo, 2021). The main components of miRISC include miRNA, miRNA-repressible mRNA, GW182, and Ago2 (Zhang et al, 2015;Babuta and Szabo, 2021), and we previously demonstrated that alcohol induces the expression of GW182 (Bukong et al, 2013). It is possible that alcohol is modulating the expression of these proteins to induce miRs sorting into exosomes.…”

“…miRs are small noncoding RNAs that regulate gene expression and are involved in various physiological processes (Szabo and Bala, 2013;Babuta and Szabo, 2021). Altered miRNA expression has been found in ALD (Bala and Szabo, 2012;Bala et al, 2016;Satishchandran et al, 2018).…”

Epigenetics of alcohol-related liver diseases

“…Alcohol promotes inflammation, steatosis, and subsequently fibrosis by regulating multiple miRNAs. [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] In alcohol-fed murine models, miR-132 and miR-155 levels were upregulated in Kupffer cells. 92 MiR-155 enhances the proinflammatory effects of alcohol on Kupffer cells.…”