Regulation of gene expression of the receptor for advanced glycation end products (RAGE) in human lymphocytes and monocytes

Abstract

Diabetes patients are more prone to infections and present an exacerbated immune-inflammatory trait. These characteristics are directly related to numerous complications in these patients, including recurrent severe infections, greater risk of sepsis, increased prevalence and severity of periodontal diseases and atherosclerosis, The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor expressed by various cell types, including those of the innate and adaptive immunity. RAGE mediates the biological effects of the advanced glycation end products (AGE) at the cellular level and also interacts with other ligands involved in inflammation. RAGE functions as a pattern recognition receptor, similarly to Toll-like receptors (TLRs), except that all the known ligands for RAGE have endogenous origin. In fact, other than AGEs, RAGE also recognizes cell destruction and degradation products, such as S100/calgranulin and HMBG1, which are damage associated molecular patterns (DAMPs) that are also recognized by TLRs and capable of activating the innate immune response. RAGE signaling is considered an important link between innate and adaptive immunity and there are evidence that its expression levels are increased in various metabolic conditions, such as diabetes, dyslipidemia and ageing. There is a gap on the information on the regulation of RAGE expression by infectious and inflammatory stimuli. This information is relevant to provide a better understanding of biological mechanisms controlling the immune response, as RAGE can function as an amplifier of the immune response, particularly in conditions associated with accumulation of its ligands (AGEs and DAMPs), contributing to the aggravation of complications in diabetes, aging and high cholesterol. Thus, our main hypothesis in this proposal is: RAGE, TLR and cytokine receptors regulate RAGE gene expression and cell proliferation of T lymphocytes and monocytes, with a synergistic effect upon simultaneous activation of multiple receptors.