Hepatocytes subjected to chronic-plus-binge ethanol feeding release microvesicles enriched with mtDNA.121 These mtDNA-enriched EVs promote neutrophil recruitment, thereby exacerbating liver injury.121 In murine models of AH, elevated levels of circulating EVs were observed, and hepatocyte-derived EVs were enriched in mtDNA.12 These mtDNA-enriched EVs activated TLR9 in macrophages, leading to increased production of pro-inflammatory cytokines such as IL-1 and IL-17.12 Furthermore, the EVs promoted HSCs activation, contributing to both liver fibrosis and inflammation.12 Additionally, hepatocytes treated with ethanol also release EVs enriched with CD40 ligand (CD40L), which induce M1 phenotypic switch in macrophages, characterised by elevated expression of pro-inflammatory cytokines.122 Increased levels of CD40L-expressing EVs have also been detected in the serum of patients with AH, suggesting their potential clinical relevance.122 In a murine model of AH, specific miRNA cargos within EVs derived from hepatocytes, such as miR-27a and miR-181, were found to contribute to HSC activation by repressing Nlrp2 expression, a marker of quiescent HSCs.12 Moreover, hepatocytes exposed to alcohol secrete miR-122-containing EVs that sensitise liver macrophages to LPS, leading to increased levels of pro-inflammatory cytokines through the inhibition of the heme oxygenase-1 pathway.123 Additionally, EVs released from intestinal epithelial cells exposed to alcohol have been shown to decrease hepatocyte viability and increase lipid deposition,124 highlighting the potential crosstalk between the gut and liver in the context of ALD pathogenesis
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