The Lung Extracellular Matrix Shows Increased IsoDGR Modifications with Age
Cells react to the state of the extracellular matrix that they reside in. Changes to the molecules of the extracellular matrix do take place with age, and as a whole this aspect of aging is comparatively poorly studied and understood. Researchers here characterize one specific molecular alteration of extracellular matrix molecules that is found in aged lung tissue, show that it changes cell behavior for the worse via interaction with the cell surface, and demonstrate that an immunotherapy approach to remove these problem molecules reduces age-related pathology in an animal model of lung disease.
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. IsoAsp-Gly-Arg (IsoDGR) modification has previously been observed in structural proteins such as fibronectin, laminin, tenascin C, and several other extracellular matrix (ECM) constituents of human arteries, leading to increased leukocyte infiltration of coronary vessels. These ECM proteins are also essential components of human lungs, which consist of a complex anatomy of fibrous proteins (collagen, elastin), glycoproteins (fibronectin, laminin), glycosaminoglycans (heparin, hyaluronic acid), and proteoglycans (perlecan, versican). These long-lived lung proteins are particularly susceptible to isoDGR accumulation, potentially triggering macrophage infiltration and expression of pro-inflammatory cytokines. Indeed, isoDGR structurally mimics the Arg-Gly-Asp (RGD) integrin binding motif, and may therefore mediate leukocyte recruitment to induce pulmonary inflammaging, but it is unknown whether this motif drives age-linked lung diseases such as fibrosis and emphysema
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.