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  • Title: Myeloid-Cell-Specific IL-6 Signaling Promotes MicroRNA-223-Enriched Exosome Production to Attenuate NAFLD-Associated Fibrosis.
    Author: Hou X, Yin S, Ren R, Liu S, Yong L, Liu Y, Li Y, Zheng MH, Kunos G, Gao B, Wang H.
    Journal: Hepatology; 2021 Jul; 74(1):116-132. PubMed ID: 33236445.
    Abstract:
    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.
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