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Review
. 2021 Feb;41(2):614-627.
doi: 10.1161/ATVBAHA.120.315527. Epub 2020 Dec 17.

Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: With Stops Along the Way in the Lung, Heart, Blood Vessels, and Adipose Tissue

Divya Roy  1   2 , Ravichandran Ramasamy  1 , Ann Marie Schmidt  1
Affiliations
Review

Journey to a Receptor for Advanced Glycation End Products Connection in Severe Acute Respiratory Syndrome Coronavirus 2 Infection: With Stops Along the Way in the Lung, Heart, Blood Vessels, and Adipose Tissue

Divya Roy et al. Arterioscler Thromb Vasc Biol. 2021 Feb.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and the pandemic has yet to wane. Despite its associated significant morbidity and mortality, there are no definitive cures and no fully preventative measures to combat SARS-CoV-2. Hence, the urgency to identify the pathobiological mechanisms underlying increased risk for and the severity of SARS-CoV-2 infection is mounting. One contributing factor, the accumulation of damage-associated molecular pattern molecules, is a leading trigger for the activation of nuclear factor-kB and the IRF (interferon regulatory factors), such as IRF7. Activation of these pathways, particularly in the lung and other organs, such as the heart, contributes to a burst of cytokine release, which predisposes to significant tissue damage, loss of function, and mortality. The receptor for advanced glycation end products (RAGE) binds damage-associated molecular patterns is expressed in the lung and heart, and in priming organs, such as the blood vessels (in diabetes) and adipose tissue (in obesity), and transduces the pathological signals emitted by damage-associated molecular patterns. It is proposed that damage-associated molecular pattern-RAGE enrichment in these priming tissues, and in the lungs and heart during active infection, contributes to the widespread tissue damage induced by SARS-CoV-2. Accordingly, the RAGE axis might play seminal roles in and be a target for therapeutic intervention in SARS-CoV-2 infection.

Keywords: COVID-19; angiotensin-converting enzyme 2; endothelial cells; interferon regulatory factors; pandemics.

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Conflict of interest statement

A.M. Schmidt and R. Ramasamy hold patents and patent applications related to antagonism of receptor for advanced glycation end products. The other author reports no conflict.

Figures

Figure.
Figure.
Receptor for advanced glycation end products (RAGE) and the many roads to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent studies from SARS-CoV-2-infected human subjects have demonstrated that elevation of damage-associated molecular patterns (DAMP) ligands of RAGE, such as HMGB1, S100A8, S100A9, S100A11, S100A12, and S100B in the lung tissue, and plasma/serum are associated with disease severity and risk of death. Hence, in active infection, in part I of the hypothesized RAGE response in acute infection (top), these DAMP ligands of RAGE may exacerbate the local responses to infection in organs such as the lung and heart, leading to severe cell stress/death. The known sequelae of RAGE activities, in part through the actions of NF-kB (nuclear factor-kappa B), lead to endothelial dysfunction (permeability, prothrombotic and proinflammatory state); immune cell activation, oxidative stress, and upregulation of distinct factors such as EGR1 (early growth response 1), which coordinates much of the adverse responses to hypoxia and ischemia. The recent observation that RAGE ligands upregulate IRF7 (interferon regulatory factor 7) in immune cells suggests that DAMP RAGE ligands might aggravate disease in SARS-CoV-2 infection. Within the sphere of RAGE biology, many of these same DAMP ligands also accumulate in chronic inflammatory and metabolic disorders. In part 2 of the hypothesized RAGE priming mechanisms in diabetes/hyperglycemia and obesity (bottom), the inexorable accumulation of advanced glycation end products (AGEs) and other DAMP RAGE ligands relevant to cardiometabolic perturbation may prime the organs for amplification of inflammatory and tissue-damaging mechanisms upon SARS-CoV-2 infection. Hence, blockade of RAGE, during immunometabolic priming in diabetes/obesity, or during active SARS-CoV-2 infection, might be efficacious in tempering the damage from acute infection and in preventing diabetes/obesity-mediated amplification of coronavirus disease 2019 (COVID-19) severity. These hypotheses are open questions amenable to investigation. EC indicates endothelial cell; and TLR, toll-like receptor.
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