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AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment

机译：DNA损伤的AIM2炎症小体监测影响神经发育

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摘要

The sensing of DNA damage by the AIM2 inflammasome promotes the death of central nervous system cells and is required for normal brain development.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 pyroptosis(1-4). 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.
机译：AIM2炎性小体对DNA的损伤感测促进中枢神经系统细胞的死亡，这是正常大脑发育所必需的。神经发育的特征是神经细胞增殖和分化的速度加快，随后是大量细胞死亡，其中近一半以上产生的脑细胞被修剪掉。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成熟和功能仍然未知。在这里，我们显示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，称为发烧（1-4）。我们观察到神经发育中明显的AIM2炎性体激活，发现这种DNA损伤传感器中的缺陷导致小鼠焦虑相关行为。此外，我们显示，AIM2炎性小体通过其对gasdermin-D的调节，而不是通过其参与细胞因子IL-1和/或IL-18的产生而特别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基因受损的CNS细胞中的作用一致，我们发现有缺陷的AIM2炎性体信号转导响应DNA损伤诱导剂和神经发育过程而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。我们的发现将炎性小体通过其在去除遗传受损细胞中的作用确定为建立适当形成的中枢神经系统的关键角色。

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  • 来源
    《Nature》 |2020年第7805期|647-652|共6页
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  • 作者单位

    Univ Virginia Sch Med Dept Neurosci Ctr Brain Immunol & Glia BIG Charlottesville VA 22908 USA|Univ Virginia Sch Med Neurosci Grad Program Charlottesville VA 22908 USA;

    Univ Virginia Sch Med Dept Neurosci Ctr Brain Immunol & Glia BIG Charlottesville VA 22908 USA;

    Univ Virginia Sch Med Dept Neurosci Ctr Brain Immunol & Glia BIG Charlottesville VA 22908 USA|Univ Virginia Sch Med Med Scientist Training Program Charlottesville VA 22908 USA|Univ Virginia Sch Med Immunol Training Program Charlottesville VA 22908 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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