High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice.

Abstract

High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell-specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis attributed to drug-induced liver injury (DILI), cholestasis, ASH, or nonalcoholic steatohepatitis (NASH). HMGB1 was up-regulated and secreted mostly by hepatocytes and Kupffer cells (KCs) following CCl4 treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep ) or in myeloid cells (Hmgb1ΔMye ) partially protected, whereas ablation in both (Hmgb1ΔHepΔMye ) prevented liver fibrosis in vivo. Coculture with hepatocytes or KCs from CCl4 -injected wild-type (WT) mice up-regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl4 -injected Hmgb1ΔHep or with KCs from CCl4 -injected Hmgb1ΔMye mice partially blunted this effect. Rage ablation in HSCs (RageΔHSC ) and RAGE neutralization prevented liver fibrosis. Last, we identified that HMGB1 stimulated HSC migration and signaled through RAGE to up-regulate Collagen type I expression by activating the phosphorylated mitogen-activated protein kinase kinase (pMEK)1/2, phosphorylated extracellular signal-regulated kinase (pERK)1/2 and pcJun signaling pathway. Conclusion: Hepatocyte and KC-derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling through RAGE in HSCs to activate the pMEK1/2, pERK1/2 and pcJun pathway and increase Collagen type I deposition.

• Authors: Xiaodong Ge, Elena Arriazu, Fernando Magdaleno, Daniel J Antoine, Rouchelle Dela Cruz, Neil Theise, Natalia Nieto
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 68 Issue 6 Pg. 2380-2404 (12 2018) ISSN: 1527-3350 [Electronic] United States
• PMID: 29774570 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 by the American Association for the Study of Liver Diseases.

Chemical References

• Collagen Type I
• HMGB1 Protein
• Receptor for Advanced Glycation End Products

Topics

• Animals
• Carbon Tetrachloride Poisoning (metabolism)
• Case-Control Studies
• Collagen Type I (metabolism)
• HMGB1 Protein (metabolism)
• Hepatic Stellate Cells (metabolism)
• Hepatocytes (metabolism)
• Humans
• Kupffer Cells (metabolism)
• Liver Cirrhosis (etiology, metabolism)
• MAP Kinase Signaling System
• Mice
• Myeloid Cells (metabolism)
• Receptor for Advanced Glycation End Products (metabolism)