p75 Neurotrophin Receptor Signaling Regulates Hepatic Myofibroblast Proliferation and Apoptosis in Recovery from Rodent Liver Fibrosis
p75 Neurotrophin Receptor Signaling Regulates Hepatic Myofibroblast Proliferation and Apoptosis in Recovery from Rodent Liver Fibrosis
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DOI：
10.1002/hep.22701
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发表时间：
2009-03-01
期刊：
影响因子：
13.5
通讯作者：
Iredale, John P.
中科院分区：
文献类型：
--
作者：
Kendall, Timothy J.;Hennedige, Selina;Iredale, John P.
肝肌成纤维细胞的凋亡是肝纤维化消退的关键。我们发现人肝成肌细胞共表达p75(NTR)(p75神经营养素受体)和山梨素，从而促进对成熟和前神经生长因子(ProNGF)的不同反应。虽然成熟的NGF是促凋亡的，但proNGF保护人肝成肌纤维细胞免受凋亡的影响。此外，在实验性肝纤维化的恢复过程中，proNGF的减少与肝成纤维细胞的凋亡丢失是平行的。巨噬细胞衍生的基质金属蛋白酶7(MMP7)以浓度依赖的方式降解proNGF，其在肝脏中的表达与proNGF水平的下降相一致。为了确定P75(NTR)介导的事件在实验性肝纤维化中的主导作用，我们使用了一只缺乏P75(NTR)配体结合域但表达细胞内域的小鼠。我们发现，缺乏P75(NTR)配体介导的信号会导致建筑分辨率显著降低，并减少因细胞凋亡而导致的肝脏肌成纤维细胞的损失。缺乏配体活性的P75(NTR)在体内限制了肝细胞和卵圆细胞的增殖能力，而不会阻止肝星状细胞的转分化。结论：不同种类的NGF对肝肌成纤维细胞的存活有不同的影响。我们的数据表明，在肝纤维化恢复的早期阶段，MMP7对proNGF的切割改变了前/成熟NGF的平衡，促进了肝脏肌成纤维细胞的丢失。而肝纤维化是在缺乏p75(NTR)信号的情况下发生的，而p75(NTR)配体介导的缺失事件的主要作用是通过调节肝肌成纤维细胞的增殖和凋亡来延缓肝纤维化的消退，以及减少肝细胞和卵圆细胞的增殖。(《肝病》2009；49：901-910。)
Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. We show that human hepatic myofibroblasts co-express p75(NTR) (p75 neurotrophin receptor) and sortilin, thus facilitating differential responses to mature and pro nerve growth factor (proNGF). Although mature NGF is proapoptotic, proNGF protects human hepatic myofibroblasts from apoptosis. Moreover, in recovery from experimental liver fibrosis, the decrease in proNGF parallels loss of hepatic myofibroblasts by apoptosis. Macrophage-derived matrix metalloproteinase 7 (MMP7) cleaves proNGF in a concentration-dependent manner, and its expression in the liver coincides with falling proNGF levels. To define the dominant effect of P75(NTR)-mediated events in experimental liver fibrosis, we have used a mouse lacking the P75(NTR) ligand-binding domain but expressing the intracellular domain. We show that absence of P75(NTR) ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent P75(NTR) limits hepatocyte and oval cell proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Conclusion: NGF species have a differential effect on hepatic myofibroblast survival. Our data suggest that cleavage of proNGF by MMP7 during the early phase of recovery from liver fibrosis alters the pro/mature NGF balance to facilitate hepatic myofibroblast loss. Whereas fibrosis develops in the absence of p75(NTR) signaling, the dominant effects of loss of p75(NTR) ligand-mediated events are the retardation of liver fibrosis resolution via regulation of hepatic myofibroblast proliferation and apoptosis, and the reduction of hepatocyte and oval cell proliferation. (HEPATOLOGY 2009;49:901-910.)