Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Psychoneuroendocrinology. 2018 Mar;89:185-193. doi: 10.1016/j.psyneuen.2018.01.017. Epub 2018 Jan 31.
Recent evidence suggests that the cellular response to stress often elicits the unfolded protein response (UPR), which has an active role in major depression in emotionally relevant regions of the brain, such as the hippocampus. Much of the UPR activity has been found to be coalesced with the pro-inflammatory environment of the depressed brain. Specifically, downstream transcriptions of pro-inflammatory cytokines and increased regulation of candidate inflammatory mediators, such as toll-like receptors (TLRs), are promoted by the UPR. The present study examined the hippocampus associated expression profile of Tlr genes and their interaction with the UPR chaperone GRP94 in stress-induced rodent model of depression (restraint stress model). Also, the expression status of UPR related genes was evaluated in hippocampus using the same model. mRNA and protein levels of Tlr and UPR associated genes were examined by qRT-PCR and Western blot, respectively. Co-immunoprecipitation (Co-IP) method was used to determine the direct interaction between TLRs with GRP94 in depressed rat brain. The results showed that both UPR (Xbp-1, its spliced variant sXbp-1, Atf-6, Chop, and Grp94) and Tlr (2, 3, 4, 7 and 9) genes were significantly upregulated in the hippocampi of rats who were exposed to restraint stress. Similar upregulation was observed in the protein levels of the above-mentioned TLRs and the UPR chaperone protein GRP94 as well as total and phosphorylated forms of sensor proteins IRE1α and PERK. Further, a significantly increased interaction was observed between GRP94 and the activated TLR proteins. Since, increased inflammatory activity in vulnerable areas like hippocampus is coherently associated with depressed brain; our present data suggest that the UPR may be an integral part of increased activity of inflammatory regulations in depression.
最近的证据表明，细胞对压力的反应常常会引发未折叠蛋白反应（UPR），该反应在大脑中与情绪相关的区域（如海马体）的重度抑郁症中起着积极作用。研究发现，大部分 UPR 活性与抑郁大脑的促炎环境相关。具体来说，促炎细胞因子的下游转录和候选炎症介质（如 Toll 样受体（TLRs））的调节增加，都受到 UPR 的促进。本研究检查了与压力诱导的抑郁动物模型（束缚应激模型）相关的海马体中 Tlr 基因的表达谱及其与 UPR 伴侣蛋白 GRP94 的相互作用。同样，也使用相同模型评估了与 UPR 相关的基因在海马体中的表达状态。通过 qRT-PCR 和 Western blot 分别检测 Tlr 和 UPR 相关基因的 mRNA 和蛋白水平。使用共免疫沉淀（Co-IP）方法来确定抑郁大鼠脑中 TLR 与 GRP94 之间的直接相互作用。结果表明，在暴露于束缚应激的大鼠的海马体中，UPR（Xbp-1、其剪接变体 sXbp-1、Atf-6、Chop 和 Grp94）和 Tlr（2、3、4、7 和 9）基因均显著上调。在上述 TLR 和 UPR 伴侣蛋白 GRP94 以及传感器蛋白 IRE1α 和 PERK 的总蛋白和磷酸化形式的蛋白水平上也观察到了类似的上调。此外，还观察到 GRP94 与激活的 TLR 蛋白之间的相互作用显著增加。由于易损区域（如海马体）中的炎症活性增加与抑郁大脑相一致；我们目前的数据表明，UPR 可能是炎症调节活性增加的一个组成部分。
