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cGAS-STING signalling regulates microglial chemotaxis in genome instability

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Talbot, Emily J 
Joshi, Lisha 
Thornton, Peter 
Dezfouli, Mahya 
Tsafou, Kalliopi 


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.


Funder: Wellcome Trust; DOI:

Funder: University of Cambridge; DOI:

Funder: AstraZeneca PhD studentship

Funder: Ataxia Telangiectasia Society


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Nucleic Acids Research

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Oxford University Press
Royal Society Sir Henry Dale Fellowship (107643/B/15/Z)
Wellcome-Beit Prize (107643/B/15/A)
Royal Society (RGS/R1/201043)