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

Hepatology. 2021 Jul;74(1):116-132. doi: 10.1002/hep.31658. Epub 2021 Apr 27.

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.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biopsy
  • Case-Control Studies
  • Diet, High-Fat
  • Exosomes / immunology
  • Exosomes / metabolism
  • Female
  • Gene Expression Regulation / immunology
  • Healthy Volunteers
  • Hepatocytes / pathology
  • Humans
  • Interleukin-6 / blood
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Liver / cytology
  • Liver / pathology
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / pathology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / blood
  • MicroRNAs / metabolism*
  • Middle Aged
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / immunology*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Prospective Studies
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins / genetics

Substances

  • IL6 protein, human
  • Il6ra protein, mouse
  • Interleukin-6
  • MIRN223 microRNA, human
  • MIRN223 microRNA, mouse
  • MicroRNAs
  • Receptors, Interleukin-6
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • interleukin-6, mouse