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Open AccessArticle

Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions

1
Department of Microbiology and Immunology and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
2
Division of Gastroenterology, Hepatology and Nutrition and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23298, USA
3
School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei 230031, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(1), 190; https://doi.org/10.3390/cells9010190
Received: 19 December 2019 / Revised: 7 January 2020 / Accepted: 8 January 2020 / Published: 11 January 2020
(This article belongs to the Section Cellular Pathology)
Activation of hepatic macrophages represents the critical driving force to promote cholestatic liver injury. Exosomes, as important small extracellular vesicles released by almost all types of cells, contribute to intercellular communication. We previously reported that cholangiocyte-derived exosomal long noncoding RNA (lncRNA) H19 plays a vital role in disrupting bile acid homeostasis in hepatocytes and promoting the activation of hepatic stellate cells (HSCs). Exosomal H19 derived from cholangiocytes was rapidly taken up by Kupffer cells. However, the mechanistic links between exosomal lncRNA H19 and macrophage-driven inflammation in cholestasis remain unclear. Here, we reported that the hepatic H19 level was closely correlated with macrophage activation and hepatic fibrosis in both Mdr2-/- and bile duct ligation (BDL) cholestatic mouse models, as well as in human primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) patients. Exosomal H19 significantly induced the expression and secretion of chemokine (C–C motif) ligand 2 (CCL-2) and interleukin 6 (IL-6) in Kupffer cells. H19-enriched exosomes enhanced the activation M1 polarization of Kupffer cells and promoted the recruitment and differentiation of bone marrow-derived macrophages, which were inhibited by a CCL-2 pharmacological inhibitor. In conclusion, Cholangiocyte-derived exosomal H19 played a critical role in macrophage activation, differentiation, and chemotaxis through CCL-2/CCR-2 signaling pathways, which represent a therapeutic target for cholestatic liver diseases. View Full-Text
Keywords: long non-coding RNA H19; exosomes; macrophages; Kupffer cells; CCL-2 long non-coding RNA H19; exosomes; macrophages; Kupffer cells; CCL-2
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MDPI and ACS Style

Li, X.; Liu, R.; Wang, Y.; Zhu, W.; Zhao, D.; Wang, X.; Yang, H.; Gurley, E.C.; Chen, W.; Hylemon, P.B.; Zhou, H. Cholangiocyte-Derived Exosomal lncRNA H19 Promotes Macrophage Activation and Hepatic Inflammation under Cholestatic Conditions. Cells 2020, 9, 190.

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