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 CCl treatment. Neutralization of HMGB1 protected, whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1 ) or in myeloid cells (Hmgb1 ) partially protected, whereas ablation in both (Hmgb1 ) prevented liver fibrosis in vivo. Coculture with hepatocytes or KCs from CCl -injected wild-type (WT) mice up-regulated Collagen type I production by hepatic stellate cells (HSCs); yet, coculture with hepatocytes from CCl -injected Hmgb1 or with KCs from CCl -injected Hmgb1 mice partially blunted this effect. Rage ablation in HSCs (Rage ) 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.

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

“…Here, using conditional deletion of HMGB1 protein specifically in macrophages, we clearly demonstrate that macrophage‐derived HMGB1 protein does not play a key role in fibrogenesis in three different organs using a wide range of well‐established models in vivo. In contrast, a recent study by Ge et al, using macrophage‐specific genetic ablation (LysM‐CRE) or neutralization strategies demonstrates that macrophage and hepatocyte‐derived HMGB1 rather participates in liver fibrosis . Employing cell‐specific knockout of HMGB1 in macrophages in vivo, our report questions the contribution of a prototypical DAMP or pro‐inflammatory cytokine HMGB1 in the pathogenesis of fibrosis.…”

High‐Mobility Group Box‐1 and Liver Disease

“…These findings were equally replicated in four mouse models of liver fibrosis due to DILI caused by chronic CCl 4 injections or thioacetamide administration, cholestasis triggered by common bile duct ligation, and NASH induced by feeding a methionine‐ and choline‐deficient diet. Overall, these data suggested that HMGB1 has a key role in liver fibrosis …”

“…Liver fibrosis is a frequent life‐threatening complication of most chronic liver diseases. Our laboratory observed that liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus infection and primary biliary cirrhosis . Serum levels of HMGB1 were also increased in these patients compared to healthy controls, suggesting protein secretion.…”

“…Moreover, a neutralizing RAGE antibody prevented CCl 4 ‐induced fibrosis in vivo . Further experiments from our laboratory have identified HMGB1 signaling by RAGE through phospho‐mitogen‐activated protein kinase kinase (pMEK) 1/2‐pERK1/2‐p‐c‐Jun in HSCs, which appears upstream of the PI3K‐pAkt1/2/3 pathway in regulating collagen‐I production . Lastly, in the setting of HCC, HMGB1 signaling by RAGE evoked NFκB activation in HCC cells .…”

“…By binding cell‐surface receptors on immune cells, HMGB1 activates intracellular signaling pathways that regulate immune cell function, including chemotaxis and cytokine production . When HMGB1 targets hepatic stellate cells (HSCs), it induces a fibrogenic response . Currently, less is known on how it signals in hepatocytes.…”