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cGAS Mediates the Inflammatory Responses of Human Microglial Cells to Genotoxic DNA Damage

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Abstract

Genomic instability is a key driving force for the development and progression of many age-related neurodegenerative diseases and central nervous system (CNS) cancers. Recently, the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS), has been shown to detect and respond to self-DNA accumulation resulting from DNA damaging insults in peripheral cell types. cGAS has been shown to be important in the responses of microglia to DNA viruses and amyloid beta, and we have reported that it underlies the responses of human microglia to exogenous DNA. However, the role of this cytosolic sensor in the detection of self-DNA by glia is poorly understood and its ability to mediate the cellular responses of human microglia to genotoxic DNA damage has not been established. Here, we describe the ability of ionizing radiation and oxidative stress to elicit genomic DNA damage in human microglial cells and to stimulate the production of key inflammatory mediators by these cells in an NF-kB dependent manner. Importantly, we have utilized CRISPR/Cas9 and siRNA-mediated knockdown approaches and a pharmacological inhibitor of the cGAS adaptor protein stimulator of interferon genes (STING) to demonstrate that the cGAS-STING pathway plays a critical role in the generation of these microglial immune responses to such genotoxic insults. Together, these studies support the notion that cGAS mediates the detection of cytosolic self-DNA by microglia, providing a potential mechanism linking genomic instability to the development of CNS cancers and neurodegenerative disorders.

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The data used and/or analyzed during the current study available from the corresponding author on reasonable request.

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Funding

This material is based upon work supported in whole or part by the North Carolina Biotechnology Center (to IM), the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R03 NS111260 (to CR), and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number R35 GM139587 (to KAA).

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  1. Department of Biological Sciences, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC, 28223, USA

    Alexander J. Suptela, Christine Richardson, Shan Yan & Ian Marriott

  2. Department of Chemistry, University of North Carolina at Charlotte, Charlotte, NC, USA

    Yasmine Radwan & Kirill A. Afonin

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  1. Alexander J. Suptela
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  2. Yasmine Radwan
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Contributions

AJS carried out the in vitro experiments, specific capture ELISAs, immunoblot analyses, and performed data analysis. IM, CR, and SY conceived the study, contributed to the experimental design, and drafted the manuscript. KAA and YR designed, manufactured, and characterized the decoy DNA deploying constructs employed in these studies. All authors read and approved the final version of the manuscript.

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Correspondence to Ian Marriott.

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Suptela, A.J., Radwan, Y., Richardson, C. et al. cGAS Mediates the Inflammatory Responses of Human Microglial Cells to Genotoxic DNA Damage. Inflammation (2023). https://doi.org/10.1007/s10753-023-01946-8

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