cGAS-STING signalling regulates microglial chemotaxis in genome instability
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Published on: December 26, 2020
Emily J Talbot1, Lisha Joshi1, Peter Thornton2
1Department of Biochemistry, University of Cambridge, Cambridge, UK.
Abstract:
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.
Insights
Genome instability triggers neuroinflammation in microglia via the cGAS-STING pathway, driving chemokine release and affecting cell migration. This highlights a key mechanism in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Defective DNA damage signaling and repair are central to neurodegenerative diseases.
- Microglia, the brain's immune cells, mediate neuroinflammation in disease progression.
Purpose of the Study:
- To investigate how genome instability influences microglial function.
- To explore the role of the cGAS-STING axis in DNA damage-induced neuroinflammation.
Main Methods:
- Utilized human microglia-like cell models with persistent DNA damage and ATM kinase deficiency.
- Employed transcriptomic analyses and STING deletion models.
- Investigated chemokine production (CCL5, CXCL10) and cell migratory pathways.
Main Results:
- DNA damage activates the cGAS-STING pathway, inducing chronic inflammation and chemokine release in microglia.
- Type I interferon signaling, particularly IFN-β, enriches cell migratory pathways.
- STING deletion impairs microglial chemotaxis, even with ATM kinase loss.
Conclusions:
- The cGAS-STING axis is a key driver of neuroinflammation in response to DNA damage.
- Genome instability in microglia contributes to neuroinflammation and altered cell function.
- These findings offer mechanistic insights into neurodegenerative disease pathogenesis.
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