TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells
TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells
复制标题
DOI：
10.1038/jcbfm.2013.126
复制
发表时间：
2013-11-01
影响因子：
6.3
通讯作者：
Baehr, Mathias
中科院分区：
文献类型：
--
作者：
Doeppner, Thorsten R.;Kaltwasser, Britta;Baehr, Mathias
热休克蛋白70(Hsp70)对脑缺血有保护作用，这归因于其伴侣活性。然而，最近的报道也描述了Hsp70通过激活Toll样受体(TLR)的促炎作用。应用膜通透性转录反式激活因子(TAT)-HSP70分析了TAT-HSP70对小鼠脑缺血后的神经保护作用及其机制。在卒中后第3天，如果不晚于12小时，注射TAT-HSP70可减少脑梗塞体积并增强血脑屏障的完整性。后者与小胶质细胞活化减少有关，尽管在虫体和对照组动物中都观察到促炎因子TLR-2/4的上调。然而，TAT-Hsp70显著降低了下游核因子kappaB(NF-kappa B)的蛋白丰度和核转位以及核转录因子kappaB调节因子Ikappa Bα(I kappa B-α)的蛋白酶体降解。TAT-Hsp70诱导的神经保护和功能恢复仅限于4周。然而，TAT-Hsp70为成人神经前体细胞的延迟静脉移植提供了合适的细胞外环境。因此，卒中后28天移植的神经前体细胞至少有3个月的长期神经保护作用，这不是由于移植细胞的整合，而是由于移植的神经干细胞的旁分泌效应。结论：TAT-HSP70通过抑制蛋白酶体抑制减轻缺血后炎症，从而为延迟鼻咽癌移植提供合适的细胞外环境，最终达到长期神经保护的目的。
Heat-shock protein 70 (Hsp70) protects against cerebral ischemia, which is attributed to its chaperone activity. However, recent reports also describe pro-inflammatory actions of Hsp70 via activation of Toll-like receptors (TLR). Using membrane-permeable transactivator of transcription (TAT)-Hsp70, we analyzed TAT-Hsp70-induced neuroprotection and its underlying mechanism after cerebral ischemia in mice. Infusion of TAT-Hsp70 reduced infarct volume and enhanced blood-brain barrier integrity on day 3 poststroke, when given no later than 12 hours. The latter was associated with reduction of microglial activation, although upregulation of pro-inflammatory TLR-2/4 was observed both in verum and in control animals. Nevertheless, protein abundance and nuclear translocation of downstream nuclear factor kappa B (NF-kappa B) as well as proteasomal degradation of the NF-kappa B regulator Ikappa B alpha (I kappa B-alpha) were significantly reduced by TAT-Hsp70. TAT-Hsp70-induced neuroprotection and functional recovery were restricted to 4 weeks only. However, TAT-Hsp70 provided an appropriate extracellular milieu for delayed intravenous transplantation of adult neural precursor cells (NPCs). Thus, NPCs that were grafted 28 days poststroke induced long-term neuroprotection for at least 3 months, which was not due to integration of grafted cells but rather due to paracrine effects of transplanted NPCs. Conclusively, TAT-Hsp70 ameliorates postischemic inflammation via proteasome inhibition, thus providing an appropriate extracellular milieu for delayed NPC transplantation and culminating in long-term neuroprotection.