AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment.
AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment.
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DOI：
10.1038/s41586-020-2174-3
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发表时间：
2020-04
期刊：
影响因子：
64.8
通讯作者：
Lukens JR
中科院分区：
文献类型：
--
作者：
Lammert CR;Frost EL;Bellinger CE;Bolte AC;McKee CA;Hurt ME;Paysour MJ;Ennerfelt HE;Lukens JR
神经发育的特征是神经细胞增殖和分化的快速速率，然后是大规模细胞死亡的时期，其中全部产生的脑细胞中有一半以上被修剪回去。在这些神经发育事件中产生了大量的DNA损伤，细胞碎片和细胞应激的副产物，所有这些事件都可能激活免疫信号传导。对这种附带损害的免疫反应如何影响脑的成熟和功能目前仍然鲜为人知。在这里，我们表明AIM2炎症体有助于适当的大脑发育，并且这种免疫毒性应激传感器的破坏会导致行为异常。在感染的背景下，对AIM2炎症体进行了最广泛的研究，其中已知其对双链DNA（DSDNA）的激活是触发细胞因子产生的，以及一种Gasdermin-D介导的细胞死亡形式，通常称为细胞死亡形式。凋亡。我们观察到神经发育中明显的AIM2炎症体激活，发现此DNA损伤监视传感器中的缺陷导致与焦虑相关的行为。我们进一步表明，AIM2炎症体有助于中枢神经系统（CNS）稳态，特别是通过调节细胞死亡Executioner Gasdermin-D，而不是通过其参与IL-1和/或IL-18的产生。与该基因组应激传感器在遗传受损的中枢神经系统细胞清除中的作用一致，我们发现有缺陷的AIM2炎性体信号导致响应DNA损伤损伤剂和神经发育过程中的神经细胞死亡降低。此外，我们报告说，AIM2炎症小体对DNA损伤监测的破坏导致神经元中的DNA损伤过多，并增加了掺入成人大脑的神经元的数量。我们的发现将炎症体确定为通过其在去除遗传损害细胞中的作用来建立正确形成的中枢神经系统的关键参与者。
Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by a period of massive cell death where over half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and byproducts of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this collateral damage influences brain maturation and function currently remains poorly understood. Here we show that the AIM2 inflammasome contributes to proper brain development and that disruptions in this immune sensor of genotoxic stress lead to behavioral abnormalities. The AIM2 inflammasome has been most extensively studied in the context of infection, where its activation in response to double-stranded DNA (dsDNA) is known to trigger cytokine production as well as a Gasdermin-D-mediated form of cell death commonly referred to as pyroptosis. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this DNA damage surveillance sensor result in anxiety-related behaviors. We further show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of the cell death executioner Gasdermin-D, and not via its involvement in IL-1 and/or IL-18 production. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, we report that disruptions in DNA damage surveillance by the AIM2 inflammasome lead to excessive DNA damage accumulation in neurons as well as increased numbers of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a critical player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.
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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
影响因子：
32.4
作者：
Hou, Baidong;Reizis, Boris;DeFranco, Anthony L.
通讯作者：
DeFranco, Anthony L.
DOI：
10.1007/978-1-62703-520-0_21
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chen SH;Oyarzabal EA;Hong JS
通讯作者：
Hong JS
星形胶质细胞通过IL-1降低了病毒诱导的记忆功能障碍期间成人神经发生。
影响因子：
30.5
作者：
Garber C;Vasek MJ;Vollmer LL;Sun T;Jiang X;Klein RS
通讯作者：
Klein RS
影响因子：
6.3
作者：
Adamczak, Stephanie E.;Vaccari, Juan Pablo de Rivero;Keane, Robert W.
通讯作者：
Keane, Robert W.