Age-linked lung pathology is reduced by immunotherapeutic targeting of isoDGR protein damage

Abstract Aging is a significant contributor to chronic lung disorders, yet the precise molecular mechanisms remain elusive. This study investigates the impact of isoDGR motif accumulation, a form of protein damage, on age-related lung pathology using both mouse models and human lung tissues. We utilized Pcmt1-/-mice, lacking the isoDGR repair enzyme, and treated them with motif-specific antibodies, employing a range of techniques including histology, RNA sequencing, imaging, and functional analyses. Human lung tissue microarrays (TMA) were also employed to assess isoDGR associations with lung aging and fibrosis. The study revealed notable isoDGR-modified protein accumulation in lung tissue and blood vessels of Pcmt1-/-mice, accompanied by chronic low-grade inflammation, variable pulmonary edema, and reduced lifespan. This isoDGR buildup triggered mitochondrial and ribosomal dysfunction, as well as cellular senescence and apoptosis, contributing to age-related lung damage. Treatment with anti-isoDGR antibodies suppressed TLR pathway activity, alleviated cytokine-driven inflammation, restored mtDNA expression, and led to reduced lung pathology in vivo. Similarly, exposure of lung endothelial cells to isoDGR-modified fibronectin hindered oxygen consumption, escalated reactive oxygen species, and disrupted acidification; these effects were reversed by motif-specific antibodies. TMA experiments further revealed a positive correlation between isoDGR-protein levels and CD68+ macrophage infiltration in aging lung fibrosis tissues. In conclusion, this study underscores the role of isoDGR-damaged lung proteins in age-related pulmonary inflammation, utilizing both mouse models and human lung tissues. Targeting these proteins with isoDGR-specific antibodies emerges as a promising therapeutic avenue for addressing age-related pulmonary disorders in the elderly population.