Myeloid-Cell-Specific IL-6 Signaling Promotes MicroRNA-223-Enriched Exosome Production to Attenuate NAFLD-Associated Fibrosis
© 2020 by the American Association for the Study of Liver Diseases..
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:74 |
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| Enthalten in: |
Hepatology (Baltimore, Md.) - 74(2021), 1 vom: 03. Juli, Seite 116-132 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hou, Xin [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.01.2022 Date Revised 05.10.2022 published: Print-Electronic CommentIn: Hepatology. 2021 Jul;74(1):5-8. - PMID 33724502 Citation Status MEDLINE |
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| doi: |
10.1002/hep.31658 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM318031450 |
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| 100 | 1 | |a Hou, Xin |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Myeloid-Cell-Specific IL-6 Signaling Promotes MicroRNA-223-Enriched Exosome Production to Attenuate NAFLD-Associated Fibrosis |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 04.01.2022 | ||
| 500 | |a Date Revised 05.10.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Hepatology. 2021 Jul;74(1):5-8. - PMID 33724502 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 by the American Association for the Study of Liver Diseases. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSIONS: Myeloid-specific IL-6 signaling inhibits LF through exosomal transfer of antifibrotic miR-223 into hepatocytes, providing therapeutic targets for NAFLD therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Observational Study | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Ren, Ruixue |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Siqi |e verfasserin |4 aut | |
| 700 | 1 | |a Yong, Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yuxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Ming-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Kunos, George |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hua |e verfasserin |4 aut | |
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