High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice.
High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice.
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DOI：
10.1002/hep.30093
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Nieto N
中科院分区：
文献类型：
--
作者：
Ge X;Arriazu E;Magdaleno F;Antoine DJ;Dela Cruz R;Theise N;Nieto N
高迁移率族盒-1 (HMGB1) 是一种损伤相关分子模式 (DAMP)，其响应肝损伤而增加。由于 HMGB1 是晚期糖基化终末产物 (RAGE) 受体的配体，我们假设 HMGB1 的诱导可以通过 RAGE 细胞特异性信号机制参与肝纤维化的发病机制。慢性丙型肝炎病毒（HCV）感染、原发性胆汁性肝硬化（PBC）和酒精性脂肪性肝炎（ASH）患者肝脏HMGB1蛋白表达与纤维化阶段相关。在药物性肝损伤、胆汁淤积、酒精性脂肪性肝炎或非酒精性脂肪性肝炎导致的五种肝纤维化小鼠模型中，肝脏 HMGB1 蛋白表达和分泌增加。慢性四氯化碳 (CCl4) 处理后，HMGB1 上调并主要由肝细胞和库普弗细胞 (KC) 分泌。 HMGB1 的中和可起到保护作用，而注射重组 HMGB1 可促进肝纤维化。肝细胞 (Hmgb1ΔHep) 或骨髓细胞 (Hmgb1ΔMye) 中的 Hmgb1 消融可部分保护，而两者 (Hmgb1ΔHepΔMye) 中的消融可防止体内肝纤维化。与注射 CCl4 的野生型 (WT) 小鼠的肝细胞或 KC 共培养可上调肝星状细胞 (HSC) 产生的 I 型胶原蛋白；然而，与注射 CCl4 的 Hmgb1ΔHep 的肝细胞或注射 CCl4 的 Hmgb1ΔMye 小鼠的 KC 共培养部分削弱了这种效应。 HSC 中的愤怒消融 (RageΔHSC) 和 RAGE 中和可预防肝纤维化。最后，我们发现 HMGB1 刺激 HSC 迁移，并通过 RAGE 发出信号，通过激活 pMEK1/2/pERK1/2/pcJun 信号通路上调 I 型胶原蛋白表达。肝细胞和 KC 衍生的 HMGB1 通过 HSC 中的 RAGE 信号传导激活 pMEK1/2/pERK1/2/pcJun 通路并增加 I 型胶原沉积，从而参与肝纤维化的发病机制。
High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Since HMGB1 is a ligand for the receptor for advanced glycation end-products (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis via 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) and alcoholic steatohepatitis (ASH). Hepatic HMGB1 protein expression and secretion increased in five mouse models of liver fibrosis due to drug-induced liver injury, cholestasis, alcoholic steatohepatitis or non-alcoholic steatohepatitis. HMGB1 was up-regulated and secreted mostly by hepatocytes and Kupffer cells (KC) following chronic carbon tetrachloride (CCl4) treatment. Neutralization of HMGB1 protected whereas injection of recombinant HMGB1 promoted liver fibrosis. Hmgb1 ablation in hepatocytes (Hmgb1ΔHep) or myeloid cells (Hmgb1ΔMye) partially protected while ablation in both (Hmgb1ΔHepΔMye) prevented liver fibrosis in vivo. Co-culture with hepatocytes or KC from CCl4-injected wild-type (WT) mice up-regulated Collagen type I production by hepatic stellate cells (HSC); yet, co-culture with hepatocytes from CCl4-injected Hmgb1ΔHep or with KC from CCl4-injected Hmgb1ΔMye mice partially blunted this effect. Rage ablation in HSC (RageΔHSC) and RAGE neutralization prevented liver fibrosis. Lastly, we identified that HMGB1 stimulated HSC migration and signaled via RAGE to upregulate Collagen type I expression by activating the pMEK1/2/pERK1/2/pcJun signaling pathway. hepatocyte and KC-derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling via RAGE in HSC to activate the pMEK1/2/pERK1/2/pcJun pathway and increase Collagen type I deposition.
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影响因子：
29.4
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
通讯作者：
Seki E
影响因子：
13.5
作者：
Miura, Kouichi;Yang, Ling;van Rooijen, Nico;Brenner, David A.;Ohnishi, Hirohide;Seki, Ekihiro
通讯作者：
Seki, Ekihiro
影响因子：
11.2
作者：
Jube S;Rivera ZS;Bianchi ME;Powers A;Wang E;Pagano I;Pass HI;Gaudino G;Carbone M;Yang H
通讯作者：
Yang H
影响因子：
5.5
作者：
Park, JS;Gamboni-Robertson, F;Abraham, E
通讯作者：
Abraham, E
影响因子：
4.8
作者：
Hayashida, T;deCaestecker, M;Schnaper, HW
通讯作者：
Schnaper, HW