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

Xiaojiaoyang Li,Hang Yang,Yanyan Wang,Phillip B Hylemon,Xuan Wang,Emily C Gurley,Huiping Zhou,Weiwei Zhu,Runping Liu,Weidong Chen,Derrick Zhao

doi:10.3390/cells9010190

Abstract

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.

Highlights

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are critical clinical problems worldwide [1,2,3]
We previously reported that taurocholic acid (TCA) stimulated cholangiocyte proliferation and enhanced the activation of inflammatory responses via the sphingosine 1-phosphate receptor 2 (S1PR2) signaling pathway [5,6]
It is well established that activation of Kupffer cells and monocyte-derived macrophages result in the production of different cytokines and chemokines, which further promote the development of cholestatic liver injury [28,29]

Summary

Introduction

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are critical clinical problems worldwide [1,2,3]. Long non-coding RNA (lncRNA) H19, an imprinted and maternally expressed transcript [7], was predominantly expressed in cholangiocytes in the liver and was upregulated under cholestatic conditions. Our recent studies showed that aberrant expression of lncRNA H19 contributed to the bile duct ligation (BDL) and carbon tetrachloride (CCl4 ) and multidrug resistance 2 (Mdr2) deficiency-induced fibrotic liver injury and was associated with disease progression in human PSC, PBC, and biliary atresia patients [8,9,10]

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Results

Conclusion