{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Niotis G"],"funding":["EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)"],"pagination":["393-413"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12920141"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(2)"],"pubmed_abstract":["Aging and DNA damage increase the risk of chronic inflammation and autoimmunity, yet the molecular underpinnings remain unclear. In this study, we uncover a DNA damage-driven mechanism in macrophages that triggers immune autoreactivity. Here, using Er1<sup>Lyz2/</sup><sup>-</sup> mice with a macrophage-specific DNA repair defect in ERCC1-XPF, we demonstrate that monocyte-derived macrophages accumulate DNA damage, activate the immune system, drive polyclonal T cell responses and generate antinuclear autoantibodies. Proteomic and immunopeptidomic analyses reveal a distinct major histocompatibility complex class II (MHC-II) antigen repertoire enriched in nuclear and ribosomal peptides, relying on autophagy for nuclear cargo delivery to MHC-II. Aged macrophages exhibit a similar lysosomal cargo profile, linking autophagy-driven nuclear antigen presentation to immune activation. Notably, inhibiting autophagy in Er1<sup>Lyz2/</sup><sup>-</sup> mice suppresses autoimmune features, pinpointing autophagy-facilitated nuclear antigen processing as a central driver of age-related autoimmunity. These findings establish DNA damage-induced autophagy in macrophages as a pivotal mechanism linking aging to autoimmunity, unveiling potential therapeutic targets to mitigate age-related immune dysregulation."],"journal":["Nature aging"],"pubmed_title":["DNA damage in macrophages drives immune autoreactivity via nuclear antigen presentation."],"pmcid":["PMC12920141"],"funding_grant_id":["GA 812830"],"pubmed_authors":["Beli P","Garinis GA","Arvanitaki ES","Juretschke T","Schmalen A","Tsolis KC","Drakos E","Niotis G","Theodorakis E","Bertsias G","Argyros O"],"additional_accession":[]},"is_claimable":false,"name":"DNA damage in macrophages drives immune autoreactivity via nuclear antigen presentation.","description":"Aging and DNA damage increase the risk of chronic inflammation and autoimmunity, yet the molecular underpinnings remain unclear. In this study, we uncover a DNA damage-driven mechanism in macrophages that triggers immune autoreactivity. Here, using Er1<sup>Lyz2/</sup><sup>-</sup> mice with a macrophage-specific DNA repair defect in ERCC1-XPF, we demonstrate that monocyte-derived macrophages accumulate DNA damage, activate the immune system, drive polyclonal T cell responses and generate antinuclear autoantibodies. Proteomic and immunopeptidomic analyses reveal a distinct major histocompatibility complex class II (MHC-II) antigen repertoire enriched in nuclear and ribosomal peptides, relying on autophagy for nuclear cargo delivery to MHC-II. Aged macrophages exhibit a similar lysosomal cargo profile, linking autophagy-driven nuclear antigen presentation to immune activation. Notably, inhibiting autophagy in Er1<sup>Lyz2/</sup><sup>-</sup> mice suppresses autoimmune features, pinpointing autophagy-facilitated nuclear antigen processing as a central driver of age-related autoimmunity. These findings establish DNA damage-induced autophagy in macrophages as a pivotal mechanism linking aging to autoimmunity, unveiling potential therapeutic targets to mitigate age-related immune dysregulation.","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-07-09T11:41:01.366Z","creation":"2026-07-09T10:54:53.735Z"},"accession":"S-EPMC12920141","cross_references":{"pubmed":["41540279"],"doi":["10.1038/s43587-025-01053-3"]}}