Journal Article

Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19

Lu, Ying, Xiao, Yongtao, Du, Jun, Chen, Shanshan, Zhou, Huiping, Wang, Weipeng, Wang, Ying, Tian, Xinbei, Cai, Wei

2021

Overview

Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19 −/− ) and conditional deletion of H19 in macrophage (H19 ΔCD11B ) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 14/32 / 38/90 / 631/250/2520 / 64/60 / 692/699/1503/1328/1325/1377 / 96/31 / 96/95 / Animals / Antibodies / Bile / Bile ducts / Biliary atresia / Biochemistry / Biomedical and Life Sciences / Case-Control Studies / CD11b antigen / CD11b Antigen - genetics / CD11b Antigen - metabolism / cdc42 GTP-Binding Protein - genetics / cdc42 GTP-Binding Protein - metabolism / Cdc42 protein / Cell Biology / Cell Culture / Cell Proliferation / Cholestasis - complications / Diphtheria / Diphtheria toxin / Fibrosis / Guanine nucleotide-binding protein / Heparin-binding EGF-like Growth Factor - genetics / Heparin-binding EGF-like Growth Factor - metabolism / Humans / Immunology / Inflammation / Life Sciences / Liver / Liver - metabolism / Liver - pathology / Liver Cirrhosis, Biliary - genetics / Liver Cirrhosis, Biliary - metabolism / Liver Cirrhosis, Biliary - pathology / Liver Cirrhosis, Biliary - prevention & control / Liver Cirrhosis, Experimental - genetics / Liver Cirrhosis, Experimental - metabolism / Liver Cirrhosis, Experimental - pathology / Liver Cirrhosis, Experimental - prevention & control / Liver diseases / Macrophage Activation / Macrophages / Macrophages - metabolism / Macrophages - pathology / Mice / Mice, Inbred C57BL / Mice, Knockout / Monocytes / mRNA / rhoA GTP-Binding Protein - genetics / rhoA GTP-Binding Protein - metabolism / RhoA protein / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / THP-1 Cells