cGAS-STING signalling regulates microglial chemotaxis in genome instability.
In: Nucleic acids research, Jg. 52 (2024-02-09), Heft 3, S. 1188-1206
Online
academicJournal
Zugriff:
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.)
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cGAS-STING signalling regulates microglial chemotaxis in genome instability.
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Autor/in / Beteiligte Person: | Talbot, EJ ; Joshi, L ; Thornton, P ; Dezfouli, M ; Tsafou, K ; Perkinton, M ; Khoronenkova, SV |
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Zeitschrift: | Nucleic acids research, Jg. 52 (2024-02-09), Heft 3, S. 1188-1206 |
Veröffentlichung: | 1992- : Oxford : Oxford University Press ; <i>Original Publication</i>: London, Information Retrieval ltd., 2024 |
Medientyp: | academicJournal |
ISSN: | 1362-4962 (electronic) |
DOI: | 10.1093/nar/gkad1184 |
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