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DNA Damage in Macrophages Drives Immune Autoreactivity via Nuclear Antigen Presentation

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Petra Beli

LAB HEAD: Prof. Dr. Petra Beli

PROVIDER: PXD058936 | Pride | 2025-12-03

REPOSITORIES: Pride

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			Action	DRS
	20210110_QEP1_PBE_TJ_U2OS_SILAC_APEX_LC3B_ingel_S2_16h_ETO_R1_01.raw	Raw
	20210110_QEP1_PBE_TJ_U2OS_SILAC_APEX_LC3B_ingel_S2_16h_ETO_R1_02.raw	Raw
	20210110_QEP1_PBE_TJ_U2OS_SILAC_APEX_LC3B_ingel_S2_16h_ETO_R1_03.raw	Raw
	20210110_QEP1_PBE_TJ_U2OS_SILAC_APEX_LC3B_ingel_S2_16h_ETO_R1_04.raw	Raw
	20210110_QEP1_PBE_TJ_U2OS_SILAC_APEX_LC3B_ingel_S2_16h_ETO_R2_01.raw	Raw

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DNA Damage in Macrophages Drives Immune Autoreactivity via Nuclear Antigen Presentation

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