Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein S1 Induces Methylglyoxal-Derived Hydroimidazolone/Receptor for Advanced Glycation End Products (MG-H1/RAGE) Activation to Promote Inflammation in Human Bronchial BEAS-2B Cells

Abstract

The pathogenesis of coronavirus disease 2019 (COVID-19) is associated with a hyperinflammatory response. The mechanisms of SARS-CoV-2-induced inflammation are scantly known. Methylglyoxal (MG) is a glycolysis-derived byproduct endowed with a potent glycating action, leading to the formation of advanced glycation end products (AGEs), the main one being MG-H1. MG-H1 exerts strong pro-inflammatory effects, frequently mediated by the receptor for AGEs (RAGE). Here, we investigated the involvement of the MG-H1/RAGE axis as a potential novel mechanism in SARS-CoV-2-induced inflammation by resorting to human bronchial BEAS-2B and alveolar A549 epithelial cells, expressing different levels of the ACE2 receptor (R), exposed to SARS-CoV-2 spike protein 1 (S1). Interestingly, we found in BEAS-2B cells that do not express ACE2-R that S1 exerted a pro-inflammatory action through a novel MG-H1/RAGE-based pathway. MG-H1 levels, RAGE and IL-1β expression levels in nasopharyngeal swabs from SARS-CoV-2-positive and -negative individuals, as well as glyoxalase 1 expression, the major scavenging enzyme of MG, seem to support the results obtained in vitro. Altogether, our findings reveal a novel mechanism involved in the inflammation triggered by S1, paving the way for the study of the MG-H1/RAGE inflammatory axis in SARS-CoV-2 infection as a potential therapeutic target to mitigate COVID-19-associated pathogenic inflammation.

Distinct Effects of Respiratory Viral Infection Models on miR-149-5p, IL-6 and p63 Expression in BEAS-2B and A549 Epithelial Cells

“…Also, lung autopsy samples from patients with fatal COVID-19 showed alveolar-capillary barrier dysfunction, injury to alveolar and basal epithelial cells and defective tissue repair processes [ 52 ]. We observed that S1 or S2 had no effect on BEAS-2B and A549 cells viability, which is in agreement with data from Manfredelli et al [ 18 ]. In contrast to the poly (I:C) model, miR-149-5p expression was not affected by S1 or S2 transfection in BEAS-2B or A549 cells.…”

“…TLR3 further recruits tumour necrosis factor receptor (TNFR)-associated factor-6 (TRAF6) and receptor-interacting protein to activate nuclear factor kappa B (NF-κB), which regulates the production of inflammatory cytokines [ 13 ]. There are different receptors and pathways responsible for the pro-inflammatory responses of epithelial cells to SARS-CoV-2 [ 5 , 15 , 16 , 17 , 18 ]. The SARS-CoV-2 spike protein S1 subunit possesses PAMP-like properties [ 17 ].…”

“…IL-6 is a major pro-inflammatory cytokine produced by bronchial epithelial cells in response to poly (I:C) or the S1 subunit [ 18 , 19 , 20 ]. IL-6 induces multiple signalling events that drive pathogenic inflammation and immune responses [ 21 ].…”

Analysis of Crude, Diverse, and Multiple Advanced Glycation End-Product Patterns May Be Important and Beneficial

“…Lifestyle-related diseases (LSRDs), including diabetes mellitus (DM), cardiovascular disease (CVD), and nonalcoholic steatohepatitis (NASH), are a global crisis, mostly in developing countries [ 1 , 2 , 3 , 4 , 5 ]. This is attributed to people consuming excess saccharides (e.g., glucose and fructose), proteins, and lipids.…”

“…Moreover, ancient Chinese medicine considered the concept of DM symptoms [ 7 , 8 ]. Advanced glycation end products (AGEs), which are generated from saccharides/their metabolites or derivatives and proteins, are associated with LSRDs [ 1 , 2 , 3 , 4 , 5 , 9 ]. Although AGEs have been investigated since the early 20th century, when the Maillard reaction was proven [ 9 ], their relationship with human health dates back to ancient times.…”