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-ß 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.

Microglial inflammation in genome instability: A neurodegenerative perspective.

The maintenance of genome stability is crucial for cell homeostasis and tissue integrity. Numerous human neuropathologies display chronic inflammation in the central nervous system, set against a backdrop of genome instability, implying a close interplay between the DNA damage and immune responses in the context of neurological disease. Dissecting the molecular mechanisms of this crosstalk is essential for holistic understanding of neuroinflammatory pathways in genome instability disorders. Non-neuronal cell types, specifically microglia, are major drivers of neuroinflammation in the central nervous system with neuro-protective and -toxic capabilities. Here, we discuss how persistent DNA damage affects microglial homeostasis, zooming in on the cytosolic DNA sensing cGAS-STING pathway and the downstream inflammatory response, which can drive neurotoxic outcomes in the context of genome instability.