cGAS-STING signalling regulates microglial chemotaxis in genome instability.

Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-β treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system. © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

Citation

Emily J Talbot, Lisha Joshi, Peter Thornton, Mahya Dezfouli, Kalliopi Tsafou, Michael Perkinton, Svetlana V Khoronenkova. cGAS-STING signalling regulates microglial chemotaxis in genome instability. Nucleic acids research. 2024 Feb 09;52(3):1188-1206

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PMID: 38084916

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