Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages
De Silva, N.S. et al. (BioRxiv) doi: 10.1101/2022.02.17.480837
Nuclear envelope rupture
De Silva et al. identified and characterised a novel role for the nucleoskeletal protein Lamin A/C in promoting the viability and functionality of lung macrophages. Alveolar macrophages (AM) express high levels of Lamin A in mice and humans. In murine models, targeted depletion of Lamin A/C in haematopoietic or myeloid lineages led to a loss of AMs that in healthy mice exacerbates with age. Intravital imaging of in vivo AM migration revealed nuclear constrictions of up to 2-3 µm during migrations. In vitro studies constraining bone marrow derived macrophages from control or Lamin A/C deficient mice suggested that Lamin A/C expression could limit damage such as increased levels of DNA double strand breaks during AM homeostatic circulation. The loss of Lamin A/C led to AM loss via response to increased DNA damage involving a p53 dependent mechanism, but did not require the cGAS pathway, nor the absence of DNA damage and instability as measured byγH2AX phosphorylation. This suggests that in this model, the occurrence of DNA damage per se does not underlie the progressive loss of AMs but rather that the cellular response to such DNA damage, including the upregulation of CD63 and lysosomal genes plays a significant role. Interestingly, CD63 and lysosomal responses associated with autophagy were upregulated in both Lamin A/C loss or in aged lungs.
The role of aging in enhancing the consequences of Lamin A/C loss in AMs has been sufficiently demonstrated. However, the role of Lamin A/C in the aging of AMs as anticipated from the title is less clear. For instance, how does Lamin A/C level change during aging in control cells? Moreover, what is the consequence of in vitro nuclear envelope rupture in AMs or bone marrow derived macrophages from wild type mice?
The study makes excellent use of available/ published datasets to expand on observations. Such analysis of CD63 and lysosomal pathway alterations in aging or respiratory infections in humans would enhance the translational relevance of the work.
Laminopathies are associated with early mortality due to musculo-cardiovascular and nervous system pathologies, overshadowing the possible role for nuclear mechano-integrity in immune cell homeostasis. In this study, the authors uncover a significant and novel role for Lamin A/C in alveolar macrophages. While several studies have reported the reduced expression of Lamin A/C in immune cells compared to skeletal cells, recent studies in T cells have demonstrated its upregulation during immunological responses; and using targeted loss of Lamin A/C identified its key role in cellular activation and skewing differentiation pathways following immunological challenge ,. In AMs though, possibly as an adaptation to their tissue microenvironment, Lamin A/C expression was found to play a role in homeostasis. Consequently, loss of Lamin A/C in murine models leads to loss of AMs during aging and increased susceptibility to respiratory infections. This study further provides novel insights into the cellular response associated with chronic nuclear envelope rupture and DNA damage in AMs and identifies the pivotal role for CD63 and lysosomal pathway.
Reviewed by Mezida Saeed as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, the Kennedy Institute of Rheumatology and the Oxford Centre for Immuno-Oncology (OXCIO) (University of Oxford, GB) and Karolinska Institute’s Center for Infectious Medicine (CIM) & Center for Molecular Medicine (CMM). Follow her on Twitter.
 Toribio-Fernández, R., Zorita, V., Rocha-Perugini, V. et al. Lamin A/C augments Th1 differentiation and response against vaccinia virus and Leishmania major. Cell Death Dis 2018.
 Toribio-Fernández R, Herrero-Fernandez B, Zorita V, López JA, Vázquez J, Criado G, Pablos JL, Collas P, Sánchez-Madrid F, Andrés V, Gonzalez-Granado JM. Lamin A/C deficiency in CD4+ T-cells enhances regulatory T-cells and prevents inflammatory bowel disease. J Pathol. 2019