小柯机器人

瑞士洛桑联邦理工学院Andrea Ablasser研究小组发现，cGAS-STING驱动与衰老相关的炎症和神经退行性变。2023年8月2日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现，介导DNA免疫感应的cGAS-STING信号通路是衰老过程中慢性炎症和功能衰退的关键驱动因素。阻断STING可抑制衰老人体细胞和组织的炎症表型，减轻小鼠多个外周器官和大脑中与衰老相关的炎症，并改善组织功能。研究人员以衰老的大脑为重点，揭示了STING的激活会引发反应性小胶质细胞转录状态、神经变性和认知能力下降。扰动线粒体释放的细胞膜DNA会激发老龄小胶质细胞的cGAS活性，从而确定了cGAS-STING信号在衰老大脑中的作用机制。

对cGAS功能增益小鼠模型的小胶质细胞和海马的单核RNA序列分析表明，cGAS在小胶质细胞中的参与足以引导衰老相关的转录小胶质细胞状态，从而导致旁观者细胞炎症、神经毒性和记忆能力受损。这些研究结果确定了cGAS-STING通路是外周器官和大脑中与衰老相关的炎症的驱动因素，并揭示了阻断cGAS-STING信号是阻止老年期神经退行性过程的一种潜在策略。

据了解，低度炎症是老年期的标志，也是老龄相关损伤和疾病的核心驱动因素。多种因素可导致衰老相关性炎症；然而，传递异常炎症信号的分子途径及其对自然衰老的影响仍不清楚。

附：英文原文

Title: cGAS–STING drives ageing-related inflammation and neurodegeneration

Author: Gulen, Muhammet F., Samson, Natasha, Keller, Alexander, Schwabenland, Marius, Liu, Chong, Glck, Selene, Thacker, Vivek V., Favre, Lucie, Mangeat, Bastien, Kroese, Lona J., Krimpenfort, Paul, Prinz, Marco, Ablasser, Andrea

Issue&Volume: 2023-08-02

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.

DOI: 10.1038/s41586-023-06373-1

Source: https://www.nature.com/articles/s41586-023-06373-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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