Myeloid cell‐specific IL‐6 signaling promotes miR‐223‐enriched exosome production to attenuate NAFLD‐associated fibrosis

Background & aims Nonalcoholic fatty liver disease (NAFLD) is associated with elevation of many cytokines particularly IL-6; however, the role of IL-6 in NAFLD remains obscure. The aim of this study was to examine how myeloid-specific IL-6 signaling affects NAFLD via the regulation of anti-fibrotic microRNA-223 in myeloid cells. Approach & results Patients with NAFLD or nonalcoholic steatohepatitis (NASH) and healthy controls were recruited, and serum IL-6 and soluble IL-6 receptor α (sIL-6Rα) were measured. Compared to controls, serum IL-6 and sIL-6Rα levels were elevated in NAFLD/NASH patients. IL-6 levels correlated positively with the number of circulating leukocytes and monocytes. The role of IL-6 in NAFLD was investigated in Il6 knockout (KO) and Il6 receptor A (Il6ra) conditional KO mice after high-fat diet (HFD) feeding. HFD-fed Il6 KO mice had worse liver injury and fibrosis, but less inflammation compared to WT mice. Hepatocyte-specific Il6ra KO mice had more steatosis and liver injury, whereas myeloid-specific Il6ra KO mice had lower number of hepatic infiltrating macrophages and neutrophils with increased cell death of these cells but greater liver fibrosis than WT mice. Mechanistically, the increased liver fibrosis in HFD-fed myeloid-specific Il6ra KO mice was due to the reduction of anti-fibrotic miR-223 and subsequent upregulation of the miR-223 target gene transcriptional activator with PDZ-binding motif (TAZ), a well-known factor to promote NASH-fibrosis. In vitro, IL-6 treatment upregulated exosome biogenesis-related genes and subsequently promoted macrophages to release miR-223-enriched exosomes that were able to reduce pro-fibrotic TAZ expression in hepatocytes via exosomal transfer. Finally, serum IL-6 and miR-223 levels were elevated and correlated with each other in NAFLD patients. Conclusions Myeloid-specific IL-6 signaling inhibits liver fibrosis via exosomal transfer of anti-fibrotic miR-223 into hepatocytes, providing novel therapeutic targets for NAFLD therapy.