2023-08-08 スイス連邦工科大学ローザンヌ校(EPFL)
◆STINGタンパク質のブロックによって老化細胞と組織の炎症反応が抑制され、組織機能の改善が見られた。この経路はDNAの存在を検知し、免疫反応を引き起こすもので、脳の免疫細胞に影響を与えることが示され、神経変性疾患との関連も浮かび上がった。この研究は老化に伴う炎症の理解を進め、神経変性疾患の認知機能低下の遅延に向けた戦略を提供している。
<関連情報>
- https://actu.epfl.ch/news/how-immunity-contributes-to-ageing-and-neurodegene/
- https://www.nature.com/articles/s41586-023-06373-1
cGAS-STINGが加齢に関連した炎症と神経変性を引き起こす cGAS–STING drives ageing-related inflammation and neurodegeneration
Muhammet F. Gulen,Natasha Samson,Alexander Keller,Marius Schwabenland,Chong Liu,Selene Glück,Vivek V. Thacker,Lucie Favre,Bastien Mangeat,Lona J. Kroese,Paul Krimpenfort,Marco Prinz & Andrea Ablasser
Nature Published:02 August 2023
DOI:https://doi.org/10.1038/s41586-023-06373-1
Abstract
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS–STING signalling pathway, which mediates immune sensing of DNA3, 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 microglial 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-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS–STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS–STING signalling as a potential strategy to halt neurodegenerative processes during old age.
