DNA Damage in Macrophages Drives Immune Autoreactivity via Nuclear Antigen Presentation

Aging and DNA damage increase the risk of chronic inflammation and autoimmunity, yet their molecular underpinnings remain unclear. Here, we uncover a DNA damage-driven mechanism in macrophages that triggers immune autoreactivity. Using Er1Lyz2/- animals with a macrophage-specific DNA repair defect in ERCC1-XPF, we demonstrate that monocyte-derived macrophages with persistent DNA damage activate the immune system, drive polyclonal T-cell responses, and generate anti-nuclear autoantibodies. Proteomic and immunopeptidomic analyses reveal a distinct MHC-II antigen repertoire in these macrophages, 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 Er1Lyz2/⁻ 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, and unveiling potential targets for interventions to mitigate age-related immune dysregulation.