Infection susceptibility and immune senescence with advancing age replicated in accelerated aging Lmna^Dhe mice

Abstract

SummaryAging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging‐induced immunological shifts. Here, we show accelerated aging Lmna Dhe mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (≥20 month) and 2‐ to 3‐month‐old Lmna Dhe mice share near identically increased influenza A susceptibility compared with age‐matched Lmna WT control mice. Increased mortality and higher viral burden after influenza infection in Lmna Dhe mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3+ regulatory T cells, and skewed immune dominance among viral‐specific CD8+ T cells similar to the immunological phenotype of naturally aged mice. Thus, aging‐induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna Dhe mice.

Nuclear Envelope Disruption Triggers Hallmarks of Aging in Lung Alveolar Macrophages

“…We therefore hypothesized that if repeated rupture events accumulate over time in vivo, WT AM should gradually acquire a signature related to Lamin A/C CKO signature. In mice aged for 63 weeks, we detected a reduction of AM (Figure S8A), in agreement with a drop in AM levels previously reported in mice aged for more than 80 weeks (Krishnarajah et al, 2021;Wong et al, 2017;Xin et al, 2015). Next, we analyzed gene expression in AM from mice of increasing age using the Tabula Muris Senis (TMS) scRNAseq atlas, a resource characterizing aging in mouse tissues (The Tabula Muris Consortium et al, 2020).…”

Lamin A/C and the Immune System: One Intermediate Filament, Many Faces

“…These mice show increased susceptibility to infection after intranasal inoculation with the Influenza A virus. The elevated mortality and higher viral burden after influenza infection in these mice is paralleled by substantial immune-cell shifts, including reduced accumulation of lung alveolar macrophages, systemic expansion of immune suppressive Foxp3+ Tregs, and immune dominance of viral-specific CD8+ T cells [ 133 ], suggesting that lamin A/C plays an important role in the response of macrophages and T cells to viral infection. Peripheral macrophages from Lmna Dhe/− mice show increased production of inflammatory factors such as NK-κB and TNFα, linking increased inflammation triggered by defective lamin A/C function in macrophages to the origin of otitis media and hearing deficits in these mice [ 134 ].…”

Restored immune cell functions upon clearance of senescence in the irradiated splenic environment

“…Deletion of p16 INK4a in T cells enhanced antigen‐specific immune response, which suggest senescence promotes an intrinsic defect in aged T cells (Liu et al, ). Moreover, mice lacking the expression of lamin A, a nuclear scaffolding protein, present an accelerated aging phenotype with immune deficiencies (Xin, Jiang, Kinder, Ertelt, & Way, ). In comparison, whether IR‐induced senescence has a long‐term impact on the immune system is less defined.…”