cGAS-STING signalling regulates microglial chemotaxis in genome instability

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.