The Remarkable Roles of the Receptor for Advanced Glycation End Products (RAGE) and Its Soluble Isoforms in COVID-19: The Importance of RAGE Pathway in the Lung Injuries

Abstract

The respiratory symptoms of acute respiratory distress syndrome (ARDS) in the coronavirus disease 2019 (COVID-19) patients is associated with accumulation of pre-inflammatory molecules such as advanced glycation end-products (AGES), calprotectin, high mobility group box family-1 (HMGB1), cytokines, angiotensin converting enzyme 2 (ACE2), and other molecules in the alveolar space of lungs and plasma. The receptor for advanced glycation end products (RAGEs), which is mediated by the mitogen-activated protein kinase (MAPK), plays a critical role in the severity of chronic inflammatory diseases such as diabetes mellitus (DM) and ARDS. The RAGE gene is most expressed in the alveolar epithelial cells (AECs) of the pulmonary system. Several clinical trials are now being conducted to determine the possible association between the levels of soluble isoforms of RAGE (sRAGE and esRAGE) and the severity of the disease in patients with ARDS and acute lung injury (ALI). In the current article, we reviewed the most recent studies on the RAGE/ligands axis and sRAGE/esRAGE levels in acute respiratory illness, with a focus on COVID-19-associated ARDS (CARDS) patients. According to the research conducted so far, sRAGE/esRAGE measurements in patients with CARDS can be used as a powerful chemical indicator among other biomarkers for assessment of early pulmonary involvement. Furthermore, inhibiting RAGE/MAPK and Angiotensin II receptor type 1 (ATR1) in CARDS patients can be a powerful strategy for diminishing cytokine storm and severe respiratory symptoms.

Keywords: ACE2 protein; Receptor for advanced glycation end products; Respiratory distress syndrome; SARS-CoV- 2; esRAGE.

Fig. 1

Structure of RAGEs and roles of RAGE/ligand axis in pro-inflammatory pathways. A RAGE’s extracellular domain structure is composed of the constant domain (C1 and C2) and a variable domain (V); RAGE ligands (endogenous and exogenous) bind to the extracellular domains of RAGE. Cytoplasmic ligands such as mDia1 bind to the cytoplasmic domain of the RAGE. B Soluble isoforms of RAGE (sRAGE) are included esRAGE and cRAGE; esRAGE is constructed through alternative splicing on the RAGE mRNA, and cRAGE is formed through ADAM10 activity in the extracellular space. C Binding of RAGE ligands (mDia1, AGEs, etc.) to RAGE and its dimerization have significant roles in the inflammatory response in cells through regulation of cellular pathways such as PI3K/Akt/mTOR, MAPK/P38, JAC2/ STAT3, and other pointed pathways in the figure. Source The Authors

Fig. 2

Contribution of RAGE, AT1R (type 1 angiotensin receptor), ACE2 (angiotensin-converting enzyme 2), and TLR (Toll-like receptor) in alveolar epithelial cells related to COVID-19 pathogenies in a cytokine storm. A SARS-CoV-2-specific receptor (ACE2), RAGE, and TLR in the surface of type 2 alveolar epithelial cells, and related inflammatory ligands including DAMPs (damage-associated molecular patterns), PAMP (pathogen-associated molecular pattern), S100 proteins, and AGE trigger cytokine storm in the respiratory system. In the infected alveolar macrophages with SARS-CoV-2, production and releasing the pro-inflammatory cytokine such as IL-1, IL-6, IL-8, IL-10, and tumor necrosis factor alpha (TNF-α) are stimulated. B-1) Entry of the SARS-CoV-2 is mediated by ACE2/endocytosis in type 2 alveolar epithelial cells. B-2) Binding of S100 proteins, AGE, and HMGB1 to V-domain of RAGE in the surface of type 2 alveolar epithelial cells by regulating the pro-inflammatory transcription factors (Activator protein 1 (AP-1), STAT3, and NF-κB) have key roles in the production of ROS and cytokine storm. Expression of the RAGE gene in alveolar epithelial cells is increased after binding SARS-CoV-2 to ACE2. The binding of angiotensin (Ang) II to AT1R is mediated cell apoptosis, chronic inflammation, pulmonary edema, and cytokine storm in alveolar epithelial cells. Source The Authors