Kentucky Spinal Cord Injury Research Center, University of Louisville, Louisville, KY 40292, USA.
Curr Neurovasc Res. 2012 Nov;9(4):274-81. doi: 10.2174/156720212803530627.
Trauma introduces damaging stressors that compromise protein, lipid, and nucleic acid integrity. Aggregates of unfolded and misfolded proteins in the endoplasmic reticulum (ER) triggers the ER stress response (ERSR)/unfolded protein response (UPR) leading to activation of three signaling pathways mediated by PERK, ATF6, and IRE1. Initially, the ERSR/UPR is pro-homeostatic as it globally slows translation while increasing translation of chaperone proteins and inducing ER-associated degradation. If the cellular stress is not controlled, apoptosis is subsequently induced through several mechanisms, of which the most well-described is CHOP. Following spinal cord injury (SCI), mice deficient in CHOP signaling show increased spared white matter and enhanced locomotor recovery by 6 weeks. At 24 hours after SCI, ATF4 and CHOP are upregulated in under perfused microvessels. We observed vascular protection 3 days post-SCI and a significant decrease in macrophage infiltration by the end of the first week. These results suggest that modulating ER-stress signaling in endothelial cells and macrophages may protect against vascular injury and attenuate inflammation post-SCI.
创伤会引入破坏性的应激源，破坏蛋白质、脂质和核酸的完整性。内质网（ER）中未折叠和错误折叠蛋白质的聚集会触发内质网应激反应（ERSR）/未折叠蛋白反应（UPR），导致 PERK、ATF6 和 IRE1 介导的三种信号通路的激活。最初，ERSR/UPR 是有利于维持体内平衡的，因为它会全局减缓翻译，同时增加伴侣蛋白的翻译，并诱导内质网相关降解。如果细胞应激得不到控制，随后会通过几种机制诱导细胞凋亡，其中最著名的是 CHOP。在脊髓损伤（SCI）后，CHOP 信号缺失的小鼠显示出更多的白质保留和 6 周时运动功能恢复增强。在 SCI 后 24 小时，缺氧微脉管中的 ATF4 和 CHOP 上调。我们观察到 SCI 后 3 天的血管保护作用，并在第一周结束时显著减少巨噬细胞浸润。这些结果表明，调节内皮细胞和巨噬细胞中的 ER 应激信号可能有助于防止血管损伤和 SCI 后的炎症。
