Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 511447, China.
Department of Anesthesiology, The Second Affiliated Hospital of Hainan Medical University, Haikou, 570311, China.
Biochem Biophys Res Commun. 2021 Mar 5;543:72-79. doi: 10.1016/j.bbrc.2020.09.013. Epub 2021 Jan 29.
Ischemic stroke is a common disease worldwide with high mortality and disability rates. Nevertheless, pathogenesis of ischemic stroke is still vague, and finding novel therapeutic target is urgently necessary. TMEM59 (also known as dendritic cell-derived factor 1, DCF1), a type I transmembrane protein, contains a minimal 19-amino-acid peptide in its intracellular domain, and has been involved in neurological pathology. However, its biological impacts on ischemic stroke are still unknown. In this study, we provided new evidence that TMEM59 expression was significantly down-regulated upon ischemia/reperfusion (I/R). The effect of stroke insult on TMEM59 expression change was only detected in microglial cells by in vitro studies. We observed that TMEM59 knockout markedly accelerated cerebral I/R in mice induced by middle cerebral artery occlusion (MCAO), as evidenced by the elevated infarction volume, neurological deficit scores, brain water contents and neuronal death, further contributing to the abnormal behaviors for mice. We then found that microglial activation reflected by the enhanced expression of Iba-1 was dramatically potentiated by TMEM59 knockout in MCAO-treated mice. Pyroptosis was highly triggered in mice with cerebral I/R, while being further aggravated in mice with TMEM59 deletion, as proved by the considerably increased expression of NLRP3, ASC, cleaved Caspase-1, GSDMD-N, mature-IL-1β and mature-IL-18. Additionally, TMEM59 knockout mice exhibited accelerated activation of NF-κB signaling pathway compared with the wild type group of mice after MCAO operation, indicating the anabatic neuroinflammation. The effects of TMEM59 suppression on ischemic stroke were confirmed in microglial cells with exposure to oxygen-glucose deprivation/reoxygenation (OGD/R). In contrast, the in vitro studies verified that improving TMEM59 expression effectively hindered pyroptosis and inflammation in microglial cells upon OGD/R treatment. Taken together, these findings illustrated protective effects of TMEM59 against ischemic stroke through restraining pyroptosis and inflammatory response.
缺血性脑卒中是一种常见的全球性疾病，其死亡率和致残率较高。然而，缺血性脑卒中的发病机制仍不明确，因此急需寻找新的治疗靶点。TMEM59（也称为树突状细胞衍生因子 1，DCF1）是一种 I 型跨膜蛋白，其细胞内结构域含有一个最小的 19 个氨基酸肽，已被涉及神经病理学。然而，其对缺血性脑卒中的生物学影响尚不清楚。在本研究中，我们提供了新的证据表明，TMEM59 的表达在缺血/再灌注（I/R）后显著下调。通过体外研究发现，只有在小胶质细胞中才能检测到中风损伤对 TMEM59 表达变化的影响。我们观察到，TMEM59 敲除显著加速了由大脑中动脉闭塞（MCAO）诱导的小鼠脑 I/R，表现为梗死体积增加、神经功能缺损评分、脑含水量和神经元死亡增加，进一步导致小鼠行为异常。然后，我们发现，MCAO 治疗小鼠的小胶质细胞激活（表现为 Iba-1 表达增强）被 TMEM59 敲除显著增强。在发生脑 I/R 的小鼠中，焦亡被高度触发，而在 TMEM59 缺失的小鼠中则进一步加重，这被证明是由于 NLRP3、ASC、裂解 Caspase-1、GSDMD-N、成熟的 IL-1β 和成熟的 IL-18 的表达显著增加。此外，与野生型小鼠相比，MCAO 手术后 TMEM59 敲除小鼠 NF-κB 信号通路的激活明显加快，提示神经炎症加剧。在暴露于氧葡萄糖剥夺/复氧（OGD/R）的小胶质细胞中证实了 TMEM59 抑制对缺血性脑卒中的作用。相反，体外研究证实，改善 TMEM59 的表达能有效抑制 OGD/R 处理后小胶质细胞的焦亡和炎症。综上所述，这些研究结果表明 TMEM59 通过抑制焦亡和炎症反应对缺血性脑卒中具有保护作用。
