Receptor for advanced glycation end-products axis and coronavirus disease 2019 in inflammatory bowel diseases: A dangerous liaison?

Abstract

Compelling evidence supports the crucial role of the receptor for advanced glycation end-products (RAGE) axis activation in many clinical entities. Since the beginning of the coronavirus disease 2019 pandemic, there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in inflammatory gastrointestinal disorders, such as inflammatory bowel diseases (IBD). However, clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection. In the present review, we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients, the RAGE axis activation as well as the cross-talk with the renin-angiotensin system, are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme (ACE) 2. The soluble form of RAGE functions as a decoy for its ligands, and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation, particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.

Keywords: Advanced glycation; Alarmins; Angiotensin-converting enzyme 2; COVID-19; Inflammation; Inflammatory bowel diseases; Receptor for advanced glycation end-products; Receptor for advanced glycation end-products axis.

Figure 1

In inflammatory bowel diseases patients, different inflammation–prone mechanisms are known to be activated. Among them, the overexpression of receptor for advanced glycation end-products (RAGE) and the abundance of its ligands may produce a sustained activation of the axis, which can be also fueled by a non-cognate mechanism due to the pro-inflammatory rat sarcoma imbalance. These elements seem to be crucial contributors to the worsening course of inflammatory bowel diseases (IBD) patients with coronavirus disease 2019. However, other elements may dampen these inflammatory contributions, such as the high bioavailability of the soluble forms of both RAGE and angiotensin-converting enzyme 2. Soluble angiotensin-converting enzyme 2 may even interfere with severe acute respiratory syndrome coronavirus 2 entry to epithelial cells. Additionally, most if not all IBD patients are under pharmacological treatments directed to control inflammation. IBD patients deserve special attention to their diets, and as consequence, it is likely the ingestion of dietary advanced glycation-end products is also limited. RAGE: Receptor for advanced glycation end-products; RAS: Renin-angiotensin; ACE2: Angiotensin-converting enzyme 2; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; AT1R: Angiotensin II receptor type 1; AGEs: Advanced glycation-end products; sRAGE: Several soluble isoforms of this receptor.