FIGURE 8.

Acute-on-chronic drinking induces liver injury and regulates the SIRT1-miR-223 axis in neutrophils in young and middle-aged individuals. Blood samples from 29 healthy controls (16 young and 13 middle-aged people) and 32 patients with alcohol use disorder and acute intoxication (15 young and 17 middle-aged people) were analyzed (Table S3). (A) Serum ALT and AST levels, the total number and percentage of peripheral neutrophils, RT-qPCR analyses of neutrophilic SIRT1 and miR-223 and serum miR-2233 levels from healthy controls and patients with alcohol use disorder were measured. (B, C) The values in panel A were compared between different age groups (D) Correlation analyses between neutrophilic SIRT1 and miR-223 from healthy and intoxicated groups. (E) Correlation analyses between serum ALT levels and neutrophilic SIRT1 or miRNA-223 levels. Values in panels A–C represent means ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001. (F) A model depicting aging exacerbates ALD by inhibiting the neutrophilic SIRT1-miR-223 axis through the promotion of C/EBPα acetylation. ALD is associated with neutrophil infiltration, which promotes liver injury and inflammation by releasing ROS and inflammatory mediators. Interestingly, neutrophil-specific miR-223 plays a compensatory role in inhibiting ROS and inflammation. During aging, neutrophilic SIRT1 is down-regulated, such down-regulation results in decreased miR-223 expression through the induction of C/EBPα acetylation, and subsequent elevation of the miR-223 target genes including inflammatory genes (Il-6, Nlrp3, Mef2c), thereby exacerbating ALD