Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence
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/ Apoe high 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.
Authors
- Shobhit Agrawal
- Lena Wischhof (ORCID: https://orcid.org/0000-0002-2203-408X)
- Thomas Ulas (ORCID: https://orcid.org/0000-0002-9785-4197)
- Emma Dorotea Zanfi (ORCID: https://orcid.org/0000-0001-6633-9603)
- Vijay Chandrasekar (ORCID: https://orcid.org/0000-0002-5452-5107)
- Jiankai Luo (ORCID: https://orcid.org/0000-0001-5169-3095)
- Marc Beyer (ORCID: https://orcid.org/0000-0001-9704-148X)
- Hiroki Kato (ORCID: https://orcid.org/0000-0002-9571-4895)
- Andrew W. Daman (ORCID: https://orcid.org/0000-0001-8144-0574)
- Steven Z. Josefowicz (ORCID: https://orcid.org/0000-0001-7453-779X)
- Melania Capasso (ORCID: https://orcid.org/0000-0001-8659-9867)
- Elena De Domenico (ORCID: https://orcid.org/0000-0003-0336-8284)
- Hang‐Mao Lee (ORCID: https://orcid.org/0000-0002-3838-0294)
- Daniele Bano (ORCID: https://orcid.org/0000-0002-9617-5504)
- Miriam Stork
- Ala Ahrari (ORCID: https://orcid.org/0000-0001-7793-0060)
- Paolo Salomoni
- N. Ahmad Aziz (ORCID: https://orcid.org/0000-0001-6184-458X)
- Annett Halle (ORCID: https://orcid.org/0000-0002-7204-3048)
- Andreas Hermann (ORCID: https://orcid.org/0000-0002-7364-7791)
- Jonas Schulte-Schrepping (ORCID: https://orcid.org/0000-0001-7333-8924)
- Dan Ehninger (ORCID: https://orcid.org/0000-0001-7464-1335)
- Christina Georgopoulou (ORCID: https://orcid.org/0000-0003-3861-5097)
- Elvira Mass (ORCID: https://orcid.org/0000-0003-2318-2356)
- Monique M.B. Breteler (ORCID: https://orcid.org/0000-0002-0626-9305)
- Joachim L. Schultze (ORCID: https://orcid.org/0000-0003-2812-9853)
- Lorenzo Bonaguro (ORCID: https://orcid.org/0000-0001-9675-7208)
- Margit Zweyer (ORCID: https://orcid.org/0000-0001-5615-1869)
- Ketty Kessler
- Valentina Talevi (ORCID: https://orcid.org/0000-0003-4418-7439)
- Martin Fuhrmann (ORCID: https://orcid.org/0000-0001-7672-2913)
- Jenny Russ (ORCID: https://orcid.org/0000-0001-6550-761X)
- Giuliano Crispatzu (ORCID: https://orcid.org/0000-0001-8041-2125)
- Qingyi Liang
- Sophie Crux (ORCID: https://orcid.org/0000-0003-0270-4768)
- Xin Yan (ORCID: https://orcid.org/0000-0002-9135-7915)
- Pierluigi Nicotera (ORCID: https://orcid.org/0000-0003-1175-7466)
- Shahin Rafii (ORCID: https://orcid.org/0000-0001-5605-1067)
- Yunxiao Li (ORCID: https://orcid.org/0000-0002-5702-4068)
- Dina Hüsson
- Liang Qiao (ORCID: https://orcid.org/0000-0002-8765-8491)
- Ying Liu
- Manon Chevallot-Beroux
- Juntang Lin
- Yuanfang Li
- Tim Ducksch
Institutions
- University of Bonn (DE)
- Zimmer Biomet (Netherlands) (NL)
- Cornell University (US)
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- Institut für Medizinische Biometrie, Informatik und Epidemiologie (DE)
- Immune Regulation (United Kingdom) (GB)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- CRUK Lung Cancer Centre of Excellence (GB)
- First Affiliated Hospital of Henan University (CN)
- Biotronik (Germany) (DE)
- Weill Cornell Medicine (US)
- University College London (GB)
- University of Rostock (DE)
- Henan Medical University (CN)
- Epigenomics (Germany) (DE)
- Singer (United States) (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2026-08-17
- DOI
- https://doi.org/10.1038/s41593-026-02404-y
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00