The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD

Abstract

Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.

Keywords: COPD; advanced glycation end products; aging; chronic inflammation; multimorbidity; receptor for advanced glycation end products.

Figure 1

Simplified overview of sources of AGEs and other ligands that trigger RAGE signaling, leading to inflammation. Inflammation is sustained through the production of more ligands and RAGE and contributes to COPD and comorbidities. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 2

Multimorbidity in COPD is associated with common causes. Comorbidities in COPD occur in clusters, suggesting the involvement of common pathways in which chronic inflammation plays an important role.

Figure 3

Complexity of RAGE signaling. A multitude of RAGE ligands exist that activate numerous intracellular signaling pathways through various adapter proteins recruited to the intracellular domain. Through increased gene transcription, RAGE activation leads to inflammation, survival or apoptosis, migration and/or invasion, and proliferation and/or differentiation. Signal amplification is achieved through enhanced expression of RAGE itself as well as of various RAGE ligands, in which activation of NAPDH oxidase and NF-κB play a role. RAGE can also be present in the nucleus, where it has been shown to contribute to the repair of DNA double-strand breaks. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 4

RAGE isoforms and genetic variants. The AGER gene contains 11 exons. The full-length RAGE protein consists of two constant domains (C1, C2) and a variable (V) immunoglobulin domain, which together are involved in ligand binding. A transmembrane domain (TM) elicits ligand-induced oligomerization, and a cytoplasmic domain (CT) interacts with the various downstream effectors. Full-length RAGE can be cleaved into soluble RAGE by ADAM10 and MMP3, 9, and 13. Alternative splicing gives rise to endogenous soluble RAGE (esRAGE), which lacks the TM and CT, a dominant negative (DN) variant that lacks the CT, and an N-truncated variant that lacks the V-domain. Polymorphisms in the AGER promotor increase AGER expression. A SNP leading to an amino acid substitution in the V domain (G82S) increases ligand affinity and downstream signaling. Figure created with Biorender.com (accessed on 8 May 2023).

Figure 5

Causes of AGE accumulation. Dietary intake of AGEs and exposure to glycotoxins through cigarette smoke lead to AGE accumulation in tissues. Endogenous AGE formation starts with the condensation of a reducing sugar with a free amine group in a protein and proceeds through various chemical reactions and molecular rearrangements. It is accelerated under conditions of inflammation, oxidative stress, and hyperglycemia, which stimulate the formation of dicarbonyls. AGE-modified proteins are cleared by receptor mediated uptake and intracellular degradation through the ubiquitin-proteasome system, or autophagy. The resulting AGE-modified peptides are cleared from the body by the kidneys. The glyoxalase system detoxifies MGO, which is a dicarbonyl and an important AGE precursor. These clearance and detoxification systems are negatively impacted by aging and inflammation/oxidative stress. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 6

Overview of the pathophysiological effects of AGEs through modification of the extracellular matrix. AGE modification of ECM proteins leads to alterations in ECM turnover and tissue stiffness and influences various cells in contact with the ECM. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 7

Overview of interorgan crosstalk mediated by circulating AGEs. Circulating AGEs affect blood and endothelial cells through the induction of RAGE signaling, whereas AGE modification also directly influences platelets and red blood cells, as well as the function of plasma proteins including HDL, LDL, and albumin. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 8

Overview of the effects of AGEs and RAGE on various organs and their potential contribution to disease development and progression. Figure created with Biorender.com (accessed on 24 April 2023).

Figure 9

Overview of interventions aimed at AGE-RAGE. The left panel provides an overview of strategies that prevent the intake or formation of AGEs or remove AGE-induced crosslinks. The right panel provides an overview of various strategies that target RAGE. Figure created with Biorender.com (accessed on 8 May 2023).