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PreprintCited by 34Nuclear Structure and FunctionGenetics, Aging, and Longevity in Model OrganismsTelomeres, Telomerase, and Senescence

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Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages

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De Silva, Nilushi S., Nader, Guilherme P.F., Nadalin, Francesca, de Azevedo, Kevin, Couty, Mickaël, Bhargava, Anvita, Conrad, Cécile, Maurin, Mathieu, Fouillade, Charles, Londono-Vallejo, Arturo, Behrendt, Rayk, Gallwitz, Lisa, Saftig, Paul, Fernández, Beatriz Herrero, González-Granado, José María, van Niel, Guillaume, Boissonnas, Alexandre, Piel, Mathieu, Manel, Nicolas·2022·Nature Aging
DOI 10.1101/2022.02.17.480837

Preprint — published as 10.1038/s43587-023-00488-w · Paper page

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Abstract

Summary: Aging is characterized by gradual immune dysfunction and increased risk for many diseases, including respiratory infections. Genomic instability is thought to play a central role in the aging process but the mechanisms that damage nuclear DNA in aging are insufficiently defined. Cells that migrate or reside within confined environments experience forces applied to their nucleus, leading to transient nuclear envelope (NE) ruptures. NE ruptures are associated with DNA damage, and Lamin A/C is required to limit these events. Here, we show that Lamin A/C protects lung alveolar macrophages from NE rupture and hallmarks of aging. Lamin A/C ablation in immune cells results in a selective depletion of lung alveolar macrophages (AM) and a heightened susceptibility to influenza infection. Lamin A/C-deficient AM that persist display constitutive nuclear envelope rupture marks, DNA damage and p53-dependent senescence. In wild-type mice, we found that AM migrate within constricted spaces in vivo , at heights that induce NE rupture and DNA damage. AM from aged wild-type mice and from Lamin A/C-deficient mice share an upregulated lysosomal signature with CD63 expression, and we find that CD63 is required to clear damaged DNA in macrophages. We propose that induction of genomic instability by NE disruption represents a mechanism of aging in alveolar macrophages.

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Metadata

Authors
De Silva, N. S., Nader, G. P. F., Nadalin, F., de Azevedo, K., Couty, M., Bhargava, A., Conrad, C., Maurin, M., Fouillade, C., Londono-Vallejo, A., Behrendt, R., Gallwitz, L., Saftig, P., Fernández, B. H., González-Granado, J. M., van Niel, G., Boissonnas, A., Piel, M., & Manel, N.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Inserm (FR)
  • University Hospital Bonn (DE)
  • Christian-Albrechts-Universität zu Kiel (DE)
Corresponding author
Manel, Nicolas
ORCID
Venue
Nature Aging
Publisher
openRxiv
Published
2022-02-19
Volume
3
Issue
10
Pages
1251-1268
ISSN
2662-8465 (ISSN-L)
DOI
10.1101/2022.02.17.480837
OpenAlex
W4386826948
Cited by
34
References
2
Citations by year
2026: 12 · 2025: 11 · 2024: 10 · 2022: 1
FWCI
1.79
Type
journal article
Language
en
Open access
Locations
  • Nature Aging (publishedVersion)
  • SSRN Electronic Journal (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • Deposito Digital UFV (Francisco de Vitoria University) (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion)
Funders
  • British Heart Foundation
  • European Commission (H2020-MSCA-IF-2016, HORIZON2020, H2020, H2020‐MSCA‐IF, H2020-MSCA-IF-2016 DCBIO, H2020-MSCA, PI20/00306)
  • Agence Nationale de la Recherche (ANR-19-CE14-0015, ANR‐19, ANR-17-CE15-0025, ANR18, ANR-11-LABX-0043, ANR-19-CE15-0018, ANR-17, ANR-18-CE92-0022)
  • Institut National de la Santé et de la Recherche Médicale (19CS007‐00)
  • Fondation pour la Recherche Médicale (EQU202103012774)
  • Fondation ARC pour la Recherche sur le Cancer (PGA1 RF20190208474)
  • Centre National de la Recherche Scientifique
  • Institut National Du Cancer (BIO-07-ICR-1)
  • Horizon 2020 Framework Programme (MSCA-IF-2016, H2020-MSCA, H2020-MSCA-IF-2016)
  • Instituto de Salud Carlos III (PI20/00306, FPU18/00895, PI17/01395, H2020)
  • European Regional Development Fund (H2020, PI20/00306, FPU18/00895)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
nuclear envelope rupture, lamin A/C, aging, genomic instability, DNA damage, cellular senescence, p53, CD63, lysosomes, lung cancer, immune dysfunction, nuclear confinement
MeSH terms
Aging, Animals, Lung, Nuclear Envelope, Macrophages, Alveolar, Lamin Type A, Genomic Instability, Mice

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