Center for Brain Immunology and Glia (BIG), Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Neuroscience Graduate Program, School of Medicine, University of Virginia, Charlottesville, VA, USA.
Nature. 2020 Apr;580(7805):647-652. doi: 10.1038/s41586-020-2174-3. Epub 2020 Apr 8.
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. 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.
神经发育的特点是神经细胞快速增殖和分化，随后大量细胞死亡，其中超过一半的新生成的脑细胞被修剪掉。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的产物，所有这些都可能激活免疫信号。免疫对这种附带损伤的反应如何影响大脑成熟和功能尚不清楚。在这里，我们表明 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，对双链 DNA 损伤的 AIM2 炎性小体的激活会触发细胞因子的产生以及一种被称为细胞焦亡的由 gasdermin-D 介导的细胞死亡形式。我们观察到神经发育中明显的 AIM2 炎性小体激活，并且发现这种 DNA 损伤传感器的缺陷会导致小鼠出现与焦虑相关的行为。此外，我们表明，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，来专门为中枢神经系统（CNS）的稳态做出贡献。与这种基因组应激传感器在清除遗传缺陷的中枢神经系统细胞中的作用一致，我们发现有缺陷的 AIM2 炎性小体信号会导致 DNA 损伤诱导剂和神经发育过程中神经细胞死亡减少。此外，AIM2 的突变会导致神经元中 DNA 损伤的过度积累以及更多的神经元被整合到成年大脑中。我们的研究结果表明，炎性小体通过其在清除遗传缺陷细胞中的作用，成为建立适当形成的中枢神经系统的关键参与者。
