Skip to main content

Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages.

Nature aging

Authors: Nilushi S De Silva, Johan Siewiera, Chantal Alkhoury, Guilherme P F Nader, Francesca Nadalin, Kevin de Azevedo, Mickaël Couty, Helena M Izquierdo, Anvita Bhargava, Cécile Conrad, Mathieu Maurin, Konstantina Antoniadou, Charles Fouillade, Arturo Londono-Vallejo, Rayk Behrendt, Karine Bertotti, Cindy Serdjebi, François Lanthiez, Lisa Gallwitz, Paul Saftig, Beatriz Herrero-Fernández, Angela Saez, José María González-Granado, Guillaume van Niel, Alexandre Boissonnas, Matthieu Piel, Nicolas Manel

Aging is characterized by gradual immune dysfunction and increased disease risk. Genomic instability is considered central to the aging process, but the underlying mechanisms of DNA damage are insufficiently defined. Cells in confined environments experience forces applied to their nucleus, leading to transient nuclear envelope rupture (NER) and DNA damage. Here, we show that Lamin A/C protects lung alveolar macrophages (AMs) from NER and hallmarks of aging. AMs move within constricted spaces in the lung. Immune-specific ablation of lamin A/C results in selective depletion of AMs and heightened susceptibility to influenza virus-induced pathogenesis and lung cancer growth. Lamin A/C-deficient AMs that persist display constitutive NER marks, DNA damage and p53-dependent senescence. AMs from aged wild-type and from lamin A/C-deficient mice share a lysosomal signature comprising CD63. CD63 is required to limit damaged DNA in macrophages. We propose that NER-induced genomic instability represents a mechanism of aging in AMs.

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

PMID: 37723209

Participating cluster members