Immunotherapeutic targeting of aging-associated isoDGR motif in chronic lung inflammation

Abstract

Accumulation of damaged biomolecules in body tissues is the primary cause of aging and age-related chronic diseases. Since this damage often occurs spontaneously, it has traditionally been regarded as untreatable, with typical therapeutic strategies targeting genes or enzymes being ineffective in this domain. In this report, we demonstrate that an antibody targeting the isoDGR damage motif in lung tissue can guide immune clearance of harmful damaged proteins in vivo, effectively reducing age-linked lung inflammation. We observed age-dependent accumulation of the isoDGR motif in human lung tissues, as well as an 8-fold increase in isoDGR-damaged proteins in lung fibrotic tissues compared with healthy tissue. This increase was accompanied by marked infiltration of CD68+/CD11b + macrophages, consistent with a role for isoDGR in promoting chronic inflammation. We therefore assessed isoDGR function in mice that were either naturally aged or lacked the isoDGR repair enzyme. IsoDGR-protein accumulation in mouse lung tissue was strongly correlated with chronic inflammation, pulmonary edema, and hypoxemia. This accumulation also induced mitochondrial and ribosomal dysfunction, in addition to features of cellular senescence, thereby contributing to progressive lung damage over time. Importantly, treatment with anti-isoDGR antibody was able to reduce these molecular features of disease and significantly reduced lung pathology in vivo.