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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 20, 2023 |
| Title |
cGAS/STING drives ageing-related inflammation and neurodegeneration II |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
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| Overall design |
20m old aged mice were treated for 16w with DMSO or H151 over 24w. Aged mice were injected intraperitoneally with 750 nmol H151 per mouse five days a week for 8 weeks. The mice were rested for 8 weeks, and 8 weeks of treatment were repeated one more time. Nuclei from mouse brain were extracted by homogenizing mouse brain tissues in Nuclei EZ Lysis Buffer using a douncer. Nuclei were labelled with DAPI and sorted for sequencing. To enrich microglial cells, in addition to DAPI staining, nuclei were stained with anti-RBFOX3/NeuN-647.
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| Contributor(s) |
Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, Thacker VV, Favre L, Mangeat B, Kroese L, Krimpenfort P, Prinz M, Ablasser A |
| Citation(s) |
37532932 |
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| Submission date |
Jun 07, 2023 |
| Last update date |
Aug 21, 2023 |
| Contact name |
Andrea Ablasser |
| E-mail(s) |
andrea.ablasser@epfl.ch
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| Organization name |
EPFL
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| Lab |
Ablasser
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| Street address |
route Cantonale
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| City |
Lausanne |
| ZIP/Postal code |
1015 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (5)
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| GSM7467232 |
Tmem119-creERT2-cGaswt/R241E microglia mouse 1, scRNAseq |
| GSM7467233 |
Tmem119-creERT2-cGaswt/R241E microglia mouse 2, scRNAseq |
| GSM7467234 |
Tmem119-creERT2-cGaswt/wt microglia mouse 1, scRNAseq |
| GSM7467235 |
Tmem119-creERT2-cGaswt/wt microglia mouse 2, scRNAseq |
| GSM7467236 |
Tmem119-creERT2-cGaswt/wt microglia mouse 3, scRNAseq |
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| This SubSeries is part of SuperSeries: |
| GSE234422 |
cGAS/STING drives ageing-related inflammation and neurodegeneration |
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| Relations |
| BioProject |
PRJNA981208 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE234419_RAW.tar |
59.3 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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