biostudies-literatureNiotis GEC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)393-413https://www.ebi.ac.uk/biostudies/studies/S-EPMC12920141biostudies-literatureUnknown6(2)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^Lyz2/^- 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^Lyz2/^- 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.Nature agingDNA damage in macrophages drives immune autoreactivity via nuclear antigen presentation.PMC12920141GA 812830Beli PGarinis GAArvanitaki ESJuretschke TSchmalen ATsolis KCDrakos ENiotis GTheodorakis EBertsias GArgyros OfalseDNA damage in macrophages drives immune autoreactivity via nuclear antigen presentation.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^Lyz2/^- 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^Lyz2/^- 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.2026-01-01T00:00:00Z2026 Feb2026-07-09T11:41:01.366Z2026-07-09T10:54:53.735ZS-EPMC129201414154027910.1038/s43587-025-01053-3