The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest.
The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest.
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aim2相关炎症和自噬之间的平衡：CHMP2A在心脏骤停后脑损伤中的作用
DOI：
10.1186/s12974-021-02307-8
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发表时间：
2021-11-05
影响因子：
9.3
通讯作者：
Cui D
中科院分区：
文献类型：
--
作者：
Shao R;Wang X;Xu T;Xia Y;Cui D
黑色素瘤 2 缺失 (AIM2) 炎症小体的激活和神经元中自噬体清除受损对心脏骤停和自主循环恢复 (CA-ROSC) 损伤有显着影响，但 AIM2 炎症小体的调节机制以及各过程之间的关系仍知之甚少。最近，带电多泡体蛋白2A（CHMP2A）是运输所需的内体分选复合物（ESCRT）的一个亚基，被证明可以调节吞噬泡的关闭，其耗尽会导致自噬体的积累并诱导细胞死亡。在这里，我们研究了 CHMP2A 介导的自噬是否是 CA-ROSC 后 AIM2 相关炎症的潜在机制，并探讨了缺血条件下 AIM2 炎症小体与自噬之间的潜在联系。在 CA-ROSC 大鼠模型中评估了皮质中 AIM2 炎症小体的激活和自噬流。我们将 LV-Vector 或 LV-CHMP2A 病毒注射到具有立体定位坐标的运动皮层中，并将大鼠分为四组：Sham、CA、CA+LV-Vector 和 CA+LV-CHMP2A。分析了神经功能缺损评分 (NDS)、平衡木测试、大脑组织病理学损伤以及 AIM2 炎性体和促炎细胞因子的表达。 CA-ROSC 大鼠神经元中 AIM2 炎性体激活以及白介素 1β (IL-1β) 和 IL-18 释放增加与 CHMP2A 诱导的自噬水平降低同时发生。此外，沉默 CHMP2A 会导致自噬体积累并减少 AIM2 炎性体的自噬降解。与此同时，AIM2 的减少有助于自噬激活并减轻氧糖剥夺和再灌注 (OGD-Rep) 诱导的炎症。值得注意的是，CHMP2A 在皮质中的过度表达可抑制神经炎症，防止缺血性脑损伤，并改善 CA 后的神经系统结果。我们的结果支持自噬和 AIM2 信号传导之间的潜在联系，并且靶向 CHMP2A 可能为 CA-ROSC 早期阶段的神经炎症提供新的见解。在线版本包含可在 10.1186/s12974-021-02307-8 获取的补充材料。
Activation of the absent in melanoma 2 (AIM2) inflammasome and impaired autophagosome clearance in neurons contribute significantly to cardiac arrest and return of spontaneous circulation (CA-ROSC) injury, while the mechanism by which the AIM2 inflammasome is regulated and relationship between the processes remain poorly understood. Recently, charged multivesicular body protein 2A (CHMP2A), a subunit of endosomal sorting complex required for transport (ESCRT), was shown to regulate phagophore closure, and its depletion led to the accumulation of autophagosomes and induced cell death. Here, we investigated whether CHMP2A-mediated autophagy was an underlying mechanism of AIM2-associated inflammation after CA-ROSC and explored the potential link between the AIM2 inflammasome and autophagy under ischemic conditions. AIM2 inflammasome activation and autophagic flux in the cortex were assessed in the CA-ROSC rat model. We injected LV-Vector or LV-CHMP2A virus into the motor cortex with stereotaxic coordinates and divided the rats into four groups: Sham, CA, CA+LV-Vector, and CA+LV-CHMP2A. Neurologic deficit scores (NDSs), balance beam tests, histopathological injury of the brain, and expression of the AIM2 inflammasome and proinflammatory cytokines were analyzed. AIM2 inflammasome activation and increased interleukin 1 beta (IL-1β) and IL-18 release were concurrent with reduced levels of CHMP2A-induced autophagy in CA-ROSC rat neurons. In addition, silencing CHMP2A resulted in autophagosome accumulation and decreased autophagic degradation of the AIM2 inflammasome. In parallel, a reduction in AIM2 contributed to autophagy activation and mitigated oxygen–glucose deprivation and reperfusion (OGD-Rep)-induced inflammation. Notably, CHMP2A overexpression in the cortex hindered neuroinflammation, protected against ischemic brain damage, and improved neurologic outcomes after CA. Our results support a potential link between autophagy and AIM2 signaling, and targeting CHMP2A may provide new insights into neuroinflammation in the early phase during CA-ROSC. The online version contains supplementary material available at 10.1186/s12974-021-02307-8.
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DOI：
10.1038/nrm2937
发表时间：
2010-08
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1126/science.aaf7532
发表时间：
2016-11-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hu B;Jin C;Li HB;Tong J;Ouyang X;Cetinbas NM;Zhu S;Strowig T;Lam FC;Zhao C;Henao-Mejia J;Yilmaz O;Fitzgerald KA;Eisenbarth SC;Elinav E;Flavell RA
通讯作者：
Flavell RA
TRIM11 通过 p62 依赖性选择性自噬降解 AIM2，从而抑制 AIM2 炎症小体
影响因子：
8.8
作者：
Liu, Tao;Tang, Qin;Cui, Jun
通讯作者：
Cui, Jun
影响因子：
64.8
作者：
Lammert CR;Frost EL;Bellinger CE;Bolte AC;McKee CA;Hurt ME;Paysour MJ;Ennerfelt HE;Lukens JR
通讯作者：
Lukens JR
影响因子：
4.8
作者：
Harris, James;Hartman, Michelle;Lavelle, Ed C.
通讯作者：
Lavelle, Ed C.