Autophagy Activation Represses Pyroptosis through the IL-13 and JAK1/STAT1 Pathways in a Mouse Model of Moderate Traumatic Brain Injury
Autophagy Activation Represses Pyroptosis through the IL-13 and JAK1/STAT1 Pathways in a Mouse Model of Moderate Traumatic Brain Injury
复制标题
在中度创伤性脑损伤小鼠模型中，自噬激活通过 IL-13 和 JAK1/STAT1 途径抑制细胞焦亡
DOI：
10.1021/acschemneuro.0c00517
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发表时间：
2020-12-16
影响因子：
5
通讯作者：
Tao, Luyang
中科院分区：
文献类型：
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作者：
Gao, Cheng;Yan, Ya'nan;Tao, Luyang
近年来，对程序性细胞死亡（PCD）、自噬依赖性细胞死亡和焦变性细胞死亡的研究表明，这些过程与创伤性脑损伤（TBI）的病理进展密切相关。然而，它们在TBI中的串扰仍不清楚。本研究通过建立中度TBI动物模型，探讨自噬与焦亡的关系。雷帕霉素用于激活自噬过程，其在中度TBI模型中受损，并且这种治疗逆转了焦亡相关蛋白、白细胞介素-13（IL-13）和pJAK-1途径的表达，其在TBI后显著上调。IL-13水平下调，JAK-1通路被阻断，以揭示自噬抑制细胞凋亡的分子机制;这两种处理降低了细胞凋亡相关蛋白的表达水平。此外，这三种干预措施减少了神经元NLRP 3的形成，脑水肿的程度和皮质神经元变性的程度。此外，TBI后运动功能的缺陷也明显减轻。总的来说，我们的研究结果表明，自噬激活通过抑制中度TBI模型中的焦萎细胞死亡而发挥神经保护作用，并且抑制作用依赖于IL-13的下调和JAK-1-STAT-1信号通路的抑制。
The newly highlighted research into programmed cell death (PCD), autophagy dependent cell death and pyroptotic cell death, has shown that these processes are both strongly correlated with the pathological progression of traumatic brain injury (TBI). However, their cross-talk in TBI remains unclear. Here, a moderate TBI model was established to explore the relationship between autophagy and pyroptosis. Rapamycin was used to activate the process of autophagy, which was impaired in the moderate TBI model, and this treatment reversed the expression of pyroptosis associated proteins, interleukin-13 (IL-13) and the pJAK-1 pathway, which were upregulated significantly after TBI. The level of IL-13 was downregulated, and the JAK-1 pathway was blocked to reveal the molecular mechanisms by which autophagy inhibits pyroptosis; these two treatments reduced the expression levels of pyroptosis associated proteins. In addition, these three interventions reduced the formation of neuronal NLRP3, the extent of brain edema, and the degree of cortical neuron degeneration. Furthermore, the deficit in motor function post-TBI was also markedly alleviated. Collectively, our results demonstrated that autophagy activation exerts a neuroprotective effect by inhibiting pyroptotic cell death in the moderate TBI model, and the inhibitory effect was dependent on the downregulation of IL-13 and repression of the JAK-1-STAT-1 signaling pathway.