Senescent cells promote viral infection-associated inflammation and tissue damage through a robust NF-κB pathway.

Respiratory virus infections have been presenting significant global public health challenges. The virulence of SARS-CoV-2 and seasonal influenza largely relies on triggering abnormal host immune responses, particularly the production of a cytokine storm, which is notably increased in elderly patients. However, as the mechanisms underlying this age-associated exacerbation remain unclear, we investigated the role of the aging tissue microenvironment in promoting inflammation associated with viral infection. Our research, based on clinical samples, cellular experiments, and mouse models, provides evidence that the aging lung microenvironment induces severe inflammatory responses and leads to tissue damage, with senescent cells playing a crucial role in this process. Further mechanistic insights reveal that elevated levels of downstream inflammatory factors result from a significant and robust activation of the NF-κB pathway. This increase is attributed to the accumulation of reactive oxygen species in senescent cells and subsequent reduced expression of PDLIM2, an E3 ubiquitin ligase regulating P65 degradation. Finally, restoring PDLIM2 significantly inhibits viral infection-mediated inflammatory responses and organ damage in the aging body. Therefore, this study offers a novel perspective by elucidating the molecular mechanism and exploring the therapeutic potential behind viral infection-related inflammatory responses, particularly the mechanism accelerating inflammatory storms in elderly patients post-infection.