HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis
HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis
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HMGB1诱导的自噬促进肝星状细胞活化：肝纤维化的新途径
DOI：
10.1042/cs20180177
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发表时间：
2018-08-16
期刊：
影响因子：
6
通讯作者：
Yang, Changqing
中科院分区：
文献类型：
--
作者：
Li, Jing;Zeng, Chuxiong;Yang, Changqing
高迁移率族蛋白1（HMGB 1）在肝星状细胞（HSC）活化所需的自噬中起着环境依赖性的作用。然而，HMGB 1诱导的HSC自噬在肝纤维化中的意义尚未阐明。在此，我们首先记录了外周和肝内HMGB 1信号在B型肝炎病毒（HBV）相关的肝纤维化进展中的富集，并提出了HMGB 1与α-SMA（HSC活化的标志物）在肝硬化肝标本中解剖学接近的直接证据。然后，我们证明了血清来源的HMGB 1在原代小鼠HSC和人HSC细胞系（LX-2）中的自噬诱导作用，通过透射电子显微镜（TEM）下自噬空泡（AV）数量的增加和蛋白质印迹分析中脂化微管相关轻链3（LC 3-II）（自噬体的标志物）的蛋白表达上调来反映。有趣的是，在外源性HMGB 1诱导的HSC自噬过程中，可能存在内源性HMGB 1从细胞核到细胞质再到细胞外空间的易位。同时，通过激活细胞外调节蛋白激酶（ERK）/c-Jun N-末端激酶（JNK）、丝裂原活化蛋白激酶（MAPK）和抑制哺乳动物雷帕霉素靶蛋白（mTOR）/STAT 3信号通路，揭示了重组HMGB 1（rHMGB 1）增强LX-2自噬和纤维化的剂量和时间依赖性效应。此外，ERK或JNK抑制剂不仅可以抑制rHMGB 1诱导的LX-2细胞自噬和纤维化，而且可以恢复被抑制的mTOR和STAT 3通路。此外，使用LC 3-siRNA转染LX-2，我们发现HMGB 1诱导的纤维化依赖于其自噬诱导作用。最后，我们阐明了外源性HMGB 1诱导的作用中细胞外HMGB 1-受体和内源性HMGB 1对高级糖基化终产物轴的参与。我们的研究结果可能为通过靶向HSC自噬开发抗纤维化治疗开辟新的前景。
High-mobility group box-1 (HMGB1) plays a context-dependent role in autophagy, which is required for hepatic stellate cells (HSCs) activation. However, the significance of HMGB1-induced HSCs autophagy in liver fibrosis has not been elucidated. Here, we first documented an enrichment of peripheral and intrahepatic HMGB1 signal in hepatitis B virus (HBV)-related liver fibrosis progression, and presented a direct evidence of anatomic proximity of HMGB1 with a-SMA (a marker for HSCs activation) in cirrhotic liver specimens. Then, we demonstrated the autophagy-inducing effects by serum-sourced HMGB1 in both primary murine HSCs and human HSCs cell line (LX-2), reflected by increased number of autophagic vacuoles (AVs) under the transmission electron microscope (TEM) and up-regulated protein expression of lipidated microtubule-associated light chain 3 (LC3-II) (a marker for autophagosome) in Western blot analysis. Intriguingly, there is a possible translocation of endogenous HMGB1 from the nucleus to cytoplasm to extracellular space, during exogenous HMGB1-induced HSCs autophagy. Meanwhile, the dose- and time-dependent effects by recombinant HMGB1 (rHMGB1) in enhancing LX-2 autophagy and fibrogenesis have been revealed with activated extracellular regulated protein kinase (ERK)/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) and restrained mammalian target of rapamycin (mTOR)/STAT3 signaling pathways. Additionally, the ERK or JNK inhibitor could not only inhibit rHMGB1-induced autophagy and fibrogenesis in LX-2 cells, but also restore the suppressed mTOR and STAT3 pathways. Furthermore, using LC3-siRNA transfected LX-2, we found HMGB1-induced fibrogenesis is dependent on its autophagy-inducing effects. Finally, we elucidated the involvement of extracellular HMGB1-receptor for advenced glycation end product (RAGE) axis and endogenous HMGB1 in exogenous HMGB1-induced effects. Our findings could open new perspectives in developing an antifibrotic therapy by targetting the HSCs autophagy.