Myeloid‐Cell–Specific IL‐6 Signaling Promotes MicroRNA‐223‐Enriched Exosome Production to Attenuate NAFLD‐Associated Fibrosis

Background ands Aims 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 by the regulation of antifibrotic microRNA‐223 (miR‐223) in myeloid cells. Approach and Results Patients with NAFLD or 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 wild‐type mice. Hepatocyte‐specific Il6ra KO mice had more steatosis and liver injury, whereas myeloid‐specific Il6ra KO mice had a lower number of hepatic infiltrating macrophages (IMs) and neutrophils with increased cell death of these cells, but greater liver fibrosis (LF), than WT mice. Mechanistically, the increased LF in HFD‐fed, myeloid‐specific Il6ra KO mice was attributable to the reduction of antifibrotic miR‐223 and subsequent up‐regulation 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 up‐regulated exosome biogenesis‐related genes and subsequently promoted macrophages to release miR‐223‐enriched exosomes that were able to reduce profibrotic TAZ expression in hepatocytes by 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 LF through exosomal transfer of antifibrotic miR‐223 into hepatocytes, providing therapeutic targets for NAFLD therapy.