cGAS-STING signalling regulates microglial chemotaxis in genome instability

被引:12
作者
Talbot, Emily J. [1 ]
Joshi, Lisha [1 ]
Thornton, Peter [2 ]
Dezfouli, Mahya [3 ]
Tsafou, Kalliopi [4 ]
Perkinton, Michael [2 ]
Khoronenkova, Svetlana, V [1 ]
机构
[1] Univ Cambridge, Dept Biochem, Cambridge, England
[2] R&D BioPharmaceut, Neurosci, Cambridge, England
[3] AstraZeneca, Discovery Biol, Discovery Sci, BioPharmaceut R&D,Translat Genom, Gothenburg, Sweden
[4] Dept Data Sci & Quantitat Biol, Cambridge, England
基金
英国惠康基金;
关键词
DNA; ATM; SYSTEM; CELLS; ACTIVATION; DIVERSITY; MIGRATION; RECEPTOR; REVEALS; DAMAGE;
D O I
10.1093/nar/gkad1184
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-beta 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. Graphical Abstract
引用
收藏
页码:1188 / 1206
页数:19
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