Effects of Advanced Glycation End Products (AGEs) on Human Lung Macrophages: Implications for Pulmonary Inflammation

Introduction: Advanced glycation end products are a diverse, complex group of chemicals that are mostly produced by the Maillard reaction. The Maillard reaction happens when reducing sugar interacts non-enzymatically with amino acids found in proteins, lipids, or DNA. AGEs can be produced not only endogenously but also exogenously, as a result of certain cooking conditions or food processing. AGEs can interact with their receptor RAGE (receptor for AGE), expressed in various tissues including lung, inducing inflammatory effects and oxidative stress conditions that could damage target organs. Recent studies demonstrated that AGEs could be implicated in pathophysiology of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Objective: Considering that human lung macrophages (HLMs) are the most abundant immune cells in the lung, the aim of this project was to investigate the effects of AGEs on HLM activation and RAGE expression in these cells. Results: AGEs induce, in a concentration-dependent manner, the release of cytokines (IL-6, IL-1β, TNF-α) and chemokines (CXCL1, CXCL2, CXCL8) from HLMs but not their de novo synthesis, except for IL-6. AGEs affect cellular kinetic proprieties and phagocytosis. HLMs constitutively express both sRAGE (soluble form of the receptor) and flRAGE (membrane-bound form of the receptor) mRNAs, and AGEs interaction slightly upregulate sRAGE expression. RAGE protein is constitutively expressed by about 60% of HLMs. Pre-incubation of HLMs with anti-RAGE antibody inhibits the release of cytokines and chemokines induced by AGEs. Finally, HLMs store and spontaneously release AGEs. Conclusion: AGE accumulation promotes a pro-inflammatory phenotype in HLMs, potentially contributing to lung injury and respiratory dysfunction in AGEs-related diseases through the release of pro-inflammatory mediators. These findings highlight HLMs as a potential target in AGE-mediated pulmonary inflammation and suggest novel therapeutic strategies targeting the AGE-HLM axis.