Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives

Abstract

A novel infectious disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in December 2019 and declared as a global pandemic by the World Health. Approximately 15% of patients with COVID-19 progress to severe pneumonia and eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure with high morbidity and mortality. Evidence points towards a determinant pathogenic role of members of the renin-angiotensin system (RAS) in mediating the susceptibility, infection, inflammatory response and parenchymal injury in lungs and other organs of COVID-19 patients. The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, has important roles in pulmonary pathological states, including fibrosis, pneumonia and ARDS. RAGE overexpression/hyperactivation is essential to the deleterious effects of RAS in several pathological processes, including hypertension, chronic kidney and cardiovascular diseases, and diabetes, all of which are major comorbidities of SARS-CoV-2 infection. We propose RAGE as an additional molecular target in COVID-19 patients for ameliorating the multi-organ pathology induced by the virus and improving survival, also in the perspective of future infections by other coronaviruses.

Keywords: COVID-19; HMGB1; RAGE; Renin-angiotensin system (RAS); SARS-CoV-2.

Graphical abstract

Fig. 1

Overview of RAGE (receptor for advanced glycation end-products) activity in coronavirus disease 2019 (COVID-19). (A) SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) enters healthy subjects through the respiratory tract and infects secretory lung cells expressing the surface receptor ACE2 (angiotensin-converting enzyme 2) (1). The replication and release of virus cause pyroptosis of host cells (2) and consequent release of DAMPs (damage-associated molecular patterns), including HMGB1 (high mobility group 1), which are recognized by receptors, including RAGE (3,4), expressed in neighbouring epithelial cells, endothelial cells and alveolar macrophages. RAGE/HMGB1 signalling sustains the activation of alveolar macrophages and endothelial cells (5) triggering the generation of pro-inflammatory cytokines and chemokines (6), which attract monocytes, neutrophils and T cells to the site of infection promoting further inflammation (7). Alveolar macrophages and virus-specific T cells eliminate apoptotic and infected cells, respectively (8), before the virus spreads. Neutralizing antibodies produced by B cells (9) can block viral infection, and alveolar macrophages phagocyte the neutralized virus (10). This positive inflammatory feedback leads to the clearance of the virus and minimal lung damage, resulting in recovery. (B) In aged subjects or in patients with preexisting comorbidities a basal state of inflammation and high levels of circulating RAGE ligands i.e. S100 proteins, AGEs (advanced glycation end-products) and HMGB1, occur. In these conditions, SARS-CoV-2 infects, replicates and induces apoptosis of ACE2-expressing lung cells, which in turn release DAMPs (including HMGB1) (1–3). The massive presence of RAGE ligands (4) leads to over-expression and hyperactivation of RAGE in alveolar, endothelial and immune cells, including activated alveolar macrophages (5). The excessive release of cytokines and chemokines (6) may lead to abnormal accumulation of immune cells in the lung, i.e. pneumonia (7) and to a strong cytokine-dependent parenchymal epithelial and endothelial damage (8). The consequent disruption of the air-blood barrier leads to release of considerable amount of DAMPs and biomarkers of endothelial injury, such as angiotensin (Ang) II, in the alveoli and blood (9). Ang II combines with AT1R (type 1 angiotensin receptor) (10), which is over-expressed and sustained by RAGE signalling in alveolar epithelial cells, inflammatory cells, endothelial cells and fibroblasts leading to increased capillary permeability, vasoconstriction, interstitial pulmonary oedema and fibrosis, additional pulmonary and vessel cell apoptosis, and chronic inflammatory cell recruitment and activation, i.e. ARDS (acute respiratory distress syndrome). The disruption of microcapillary integrity causes the entry in the bloodstream of a cytokine storm and RAGE ligands, resulting in widespread inflammation and Ang II-dependent multi-organ damage (11). In addition, the excessive pro-inflammatory response inhibits the type I interferons (IFNs)-mediated activation of T cells leading to non-neutralizing antibodies production by B cells and reduced removal of infected cells. The RAGE-HMGB1 axis may be involved in the virus immune escape leading to virus diffusion (11) and massive virus infection of ACE2-expressing cells, culminating in patient's death.

Fig. 2

Potential mechanism underlying the interaction between RAGE (receptor for advanced glycation end-products) signalling and RAS (renin–angiotensin system) cascade in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection.