{"doi":"10.1002/hep.31658","title":"Myeloid‐Cell–Specific IL‐6 Signaling Promotes MicroRNA‐223‐Enriched Exosome Production to Attenuate NAFLD‐Associated Fibrosis","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.","journal":"Hepatology","year":2020,"id":49965,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":218,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9658,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":243197,"name":"Shi Yin","orcid":"0000-0003-0841-8391","position":1,"is_corresponding":false},{"id":244217,"name":"Ruixue Ren","orcid":null,"position":2,"is_corresponding":false},{"id":243198,"name":"Siqi Liu","orcid":"0000-0002-4184-175X","position":3,"is_corresponding":false},{"id":243199,"name":"Yong Liang","orcid":"0000-0003-3679-3084","position":4,"is_corresponding":false},{"id":243200,"name":"Yuxiao Liu","orcid":"0000-0002-4147-9797","position":5,"is_corresponding":false},{"id":243201,"name":"Yu Li","orcid":"0000-0001-6910-5933","position":6,"is_corresponding":false},{"id":162520,"name":"Ming-Hua Zheng","orcid":"0000-0003-4984-2631","position":7,"is_corresponding":false},{"id":243202,"name":"George Kunos","orcid":"0000-0003-1788-4976","position":8,"is_corresponding":false},{"id":226858,"name":"Bin Gao","orcid":"0000-0002-0505-2972","position":9,"is_corresponding":false},{"id":105553,"name":"Hua Wang","orcid":"0000-0002-2605-5697","position":10,"is_corresponding":false},{"id":243196,"name":"Xin Hou","orcid":"0000-0002-5980-5925","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T20:37:28.027635Z","pmid":"33236445","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}