Journal
JOURNAL OF NEUROSCIENCE
Volume 39, Issue 32, Pages 6378-6394Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0774-19.2019
Keywords
AIM2; inflammation; microglia; neurotoxicity; STING
Categories
Funding
- Hong Kong University of Science and Technology [R9321]
- Research Grants Council of the Hong Kong SAR [16101315, 16124916, C6009-17G, AoE/M-604/16]
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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.
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