Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages

Abstract

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.

Role of Lamin A/C on dendritic cell function in antiviral immunity

“…To selectively downregulate lamin A/C expression in specific myeloid cells, including moDCs and in vitro generated-BMDCs, we established LysM-cre +/-Lmna flox/flox mice referred to as LysM-Lmna -/or Lmna -/hereafter. LysM-Lmna -/mice exhibited physical characteristics and body weight comparable to wild-type (WT) mice with no discernible differences in the size, weight, and morphology of various immune system organs, such as the spleen or thymus, when compared to WT mice (described in [30]). Immunofluorescence analysis of cell populations in homeostasis in organs such as the spleen, mesenteric lymph nodes (mLN), lung, or bone marrow (BM) revealed no notable differences between genotypes, except for a reduction in the percentage of alveolar macrophages in adult LysM-Lmna -/animals within the studied populations [30].…”

A high-content screen reveals new regulators of nuclear membrane stability

“…Nuclear membrane rupture occurs in a range of mechanically challenging conditions in vivo , including migration through dense extracellular matrices, at the leading edge of tumors, and during nuclear migration in fission yeast, C. elegans , and mouse models of laminopathies 4,5,8,16–22 . Changes in nuclear membrane stability underlie pathogen infection, neurodegeneration, autoimmune diseases, cancer progression, and laminopathy pathologies 23,24 , suggesting nuclear envelope dynamics must be strictly regulated for proper cell functioning.…”

“…In addition, persistent rupture of micronuclear membranes can lead to catastrophic changes in chromosome structure, ongoing chromatin defects, and altered gene expression patterns that are proposed to be initiating events in some tumors and drivers of metastasis [10][11][12][13][14][15] . Nuclear membrane rupture occurs in a range of mechanically challenging conditions in vivo, including migration through dense extracellular matrices, at the leading edge of tumors, and during nuclear migration in fission yeast, C. elegans, and mouse models of laminopathies 4,5,8,[16][17][18][19][20][21][22] . Changes in nuclear membrane stability underlie pathogen infection, neurodegeneration, autoimmune diseases, cancer progression, and laminopathy pathologies 23,24 , suggesting nuclear envelope dynamics must be strictly regulated for proper cell functioning.…”

“…These pathways are even more highly activated by rupture of micronuclei, small nuclear compartments that form around missegregated chromatin in metazoans, which frequently fail to repair their membrane leaving chromatin in the cytoplasm for the duration of interphase (Guscott et al, 2022;Krupina et al, 2021). Nuclear membrane rupture has been identified in a range of mechanically challenging conditions in vivo, including migration through dense extracellular matrices, at the leading edge of tumors, and during nuclear migration in fission yeast, C. elegans, and mouse models of laminopathies (Earle et al, 2020;Nader et al, 2021a;Silva et al, 2022;Raab et al, 2016;Penfield et al, 2018;Denais et al, 2016;Kinugasa et al, 2019;Hirano et al, 2020;Chen et al, 2019;Kim et al, 2021), indicating that nuclear membrane rupture is a physiological response to a wide-range of in vivo conditions.…”