Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence

IF 20.3 1区医学 Q1 NEUROSCIENCES

Nature neuroscience Pub Date : 2026-08-17 DOI:10.1038/s41593-026-02404-y

Xin Yan, Christina Georgopoulou, Hang-Mao Lee, Ala Ahrari, Jenny Russ, Vijay Chandrasekar, Tim Ducksch, Giuliano Crispatzu, Valentina Talevi, Liang Qiao, Shobhit Agrawal, Sophie Crux, Andrew W. Daman, Lena Wischhof, Miriam Stork, Margit Zweyer, Emma Dorotea Zanfi, Manon Chevallot-Beroux, Yunxiao Li, Elena De-Domenico, Dina Hüsson, Lorenzo Bonaguro, Yuanfang Li, Jonas Schulte-Schrepping, Qingyi Liang, Ketty Kessler, Dan Ehninger, Shahin Rafii, Jiankai Luo, Andreas Hermann, Annett Halle, Ying Liu, Elvira Mass, Melania Capasso, Hiroki Kato, Joachim L. Schultze, Pierluigi Nicotera, Daniele Bano, Steven Zvi Josefowicz, Martin Fuhrmann, Thomas Ulas, Marc Beyer, Juntang Lin, Monique M. B. Breteler, N. Ahmad Aziz, Paolo Salomoni

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Abstract

Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.

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内源性逆转录病毒的抑制导致小胶质细胞的激活，从而导致炎症和细胞衰老

衰老相关的染色质压实损失与小鼠和人类组织中逆转录转座因子（rte）的抑制有关。这种RTE转录是否有助于老年大脑中常见的小胶质细胞激活尚不清楚。在这里，我们发现DAXX，一种组蛋白伴侣和RTE抑制因子，在衰老过程中下调，保持小胶质细胞稳态并抑制细胞衰老。年轻成人小胶质细胞中Daxx的缺失驱动反应性表型，其特征是rte处的染色质分解，稳态标记物的丢失，细胞周期重新进入和行为改变。这种状态导致DNA损伤和小胶质细胞耗竭，随后被daxx缺陷/Apoehigh小胶质细胞取代，显示出衰老的特征。衰老的持续诱导依赖于早幼粒细胞白血病蛋白，一种daxx相互作用因子和干扰素靶点。总之，这些发现强调了异染色质维持在保持成人小胶质细胞身份和可塑性方面的重要性，对大脑稳态、健康衰老和行为具有更广泛的意义。

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来源期刊

Nature neuroscience 医学-神经科学

CiteScore

38.60

自引率

1.20%

发文量

212

审稿时长

1 months

期刊介绍： Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.