Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences
Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences
复制标题
DOI：
10.1523/jneurosci.0774-19.2019
复制
发表时间：
2019-08-07
影响因子：
5.3
通讯作者：
Herrupu, OKarl
中科院分区：
文献类型：
--
作者：
Song, Xuan;Ma, Fulin;Herrupu, OKarl
ATM（共济失调-毛细血管扩张突变）是一种PI 3 K样激酶，因其在DNA损伤反应（DDR）中的作用而闻名，特别是在双链断裂后。ATM基因突变导致称为共济失调-毛细血管扩张症（A-T）的病症，其特征在于癌症易感性、放射敏感性、神经变性、不育和获得性免疫缺陷。我们在这里表明，先天免疫系统在A-T中也没有幸免。ATM缺陷的小胶质细胞采用活性表型，其包括促炎细胞因子的过度产生，所述促炎细胞因子对培养的神经元有毒并且可能导致A-T神经变性。ATM功能障碍导致DNA在小胶质细胞以及各种其他细胞类型的细胞质中积累。在小胶质细胞中，细胞质DNA通过DNA传感器STING（干扰素基因刺激物）引发抗病毒反应。我们发现抑制STING阻断了神经毒性细胞因子的过度产生，这支持了这种反应途径的重要性。胞质DNA还激活含有炎性小体的AIM 2（在黑素瘤2中不存在）并诱导细胞因子前体如pro-IL-1 β的蛋白水解加工。我们的研究进一步加深了我们对A-T神经变性的理解，并强调了胞质DNA在先天免疫反应中的作用。
ATM (ataxia-telangiectasia mutated) is a PI3K-like kinase best known for its role in the DNA damage response (DDR), especially after double-strand breaks. Mutations in the ATM gene result in a condition known as ataxia-telangiectasia (A-T) that is characterized by cancer predisposition, radiosensitivity, neurodegeneration, sterility, and acquired immune deficiency. We show here that the innate immune system is not spared in A-T. ATM-deficient microglia adopt an active phenotype that includes the overproduction of proinflammatory cytokines that are toxic to cultured neurons and likely contribute to A-T neurodegeneration. Causatively, ATM dysfunction results in the accumulation of DNA in the cytoplasm of microglia as well as a variety of other cell types. In microglia, cytoplasmic DNA primes an antiviral response via the DNA sensor, STING (stimulator of interferon genes). The importance of this response pathway is supported by our finding that inhibition of STING blocks the overproduction of neurotoxic cytokines. Cytosolic DNA also activates the AIM2 (absent in melanoma 2) containing inflammasome and induces proteolytic processing of cytokine precursors such as pro-IL-1 beta. Our study furthers our understanding of neurodegeneration in A-T and highlights the role of cytosolic DNA in the innate immune response.