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AIM2炎症小体监控影响神经发育
2020-04-09 13:08

美国弗吉尼亚大学John R. Lukens研究组取得一项新突破。他们发现DNA损伤导致的AIM2炎症小体监控影响神经发育。该研究于202048日发表在《自然》杂志上。

他们显示AIM2炎性小体有助于正常的大脑发育,而这种对遗传毒性应激的免疫传感器的破坏会导致行为异常。在感染过程中,响应于双链DNA损伤的AIM2炎性小体的激活触发了细胞因子的产生以及胃泌素D介导的细胞死亡形式,称为细胞焦亡。

他们观察到神经发育中明显的AIM2炎性体激活,并发现这种DNA损伤传感器的缺陷导致小鼠焦虑相关行为。此外,他们显示,AIM2炎性小体通过其对胃泌素D的调节,而不是通过其参与细胞因子IL-1/IL-18的产生而专门有助于中枢神经系统(CNS)稳态。

与此基因组压力传感器在清除遗传受损的CNS细胞中的作用一致,他们发现有缺陷的AIM2炎性体信号传导响应DNA损伤诱导剂和神经发育过程均导致神经细胞死亡减少。此外,AIM2中的突变会导致神经元中DNA损伤的过度积累以及整合到成人大脑中的神经元数量的增加。他么的发现将炎性小体确定为通过清除遗传受损细胞而建立适当形成的中枢神经系统的关键因素。

据悉,神经发育的特征是神经细胞迅速增殖和分化,然后大量细胞死亡,其中近一半的新近生成的脑细胞被清除掉。在这些神经发育事件中会产生大量的DNA损伤、细胞碎片和细胞应激副产物,所有这些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大脑的成熟和功能仍然未知。

附:英文原文

Title: AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment

Author: Catherine R. Lammert, Elizabeth L. Frost, Calli E. Bellinger, Ashley C. Bolte, Celia A. McKee, Mariah E. Hurt, Matt J. Paysour, Hannah E. Ennerfelt, John R. Lukens

Issue&Volume: 2020-04-08

Abstract: Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis1,2,3,4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.

DOI: 10.1038/s41586-020-2174-3

Source: https://www.nature.com/articles/s41586-020-2174-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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