Anti-AT1R autoantibodies and prediction of the severity of Covid-19

Papola, F.; Biancofiore, Veronica; Angeletti, Chiara; Grimaldi, Alessandro; Carucci, Anna Cecilia; Cofini, Vincenza; Necozione, Stefano; Rosciano, Alessia; Marinangeli, Franco; Cervelli, Carla

doi:10.1016/j.humimm.2021.10.006

Cited by 16 publications

(19 citation statements)

References 22 publications

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“…This proposal is consistent with the protective influence on Covid-19 severity of angiotensin receptor blockers that block the signaling of ATR1, as evidenced by a meta-analysis of several clinical trials (Guo et al, 2020), and of anti-ATR1 auto-antibodies (Papola et al, 2021), which are known to induce the increase of ATR2 expression (Sun et al, 2020b).…”

Section: The Atr2 Receptorsupporting

confidence: 70%

Is Covid-19 Severity Associated With ACE2 Degradation?

Bastolla

Chambers

Abia

et al. 2022

Front. Drug Discov.

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Covid-19 is particularly mild with children, and its severity escalates with age. Several theories have been proposed to explain these facts. In particular, it was proposed that the lower expression of the viral receptor ACE2 in children protects them from severe Covid-19. However, other works suggested an inverse relationship between ACE2 expression and disease severity. Here we review the seemingly contradicting observations on ACE2 expression at the levels of mRNA, membrane protein and serum protein in humans and rodents and try to reconcile them at the light of the Renin-Angiotensin system (RAS) and bradykinin system, which constitute an integrated inflammatory system connected by common peptidases and interacting receptors. We find that ACE2 level is not monotonically related with age but it reaches a maximum at a young age that depends on the cell type and then decreases, consistently with almost all existing data. The increase with age of the protease Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), also known as ADAM17 (a disintegrin and metalloproteinase 17) that sheds ACE2 from the cell membrane to the serum predicts that the decrease occurs before and is steeper for ACE2 cell protein than for its mRNA. This negative relation between ACE2 level and Covid-19 severity at old age is not paradoxical but it is consistent with a mathematical model that predicts that higher viral receptor does not necessarily favour virus propagation and it can even slow it down. More importantly, the angiotensin-bradykinin system is characterized by a powerful positive feedback loop that enhances inflammation through the Angiotensin and Bradykinin receptors that upregulate ADAM17, which in turn downregulates ACE2 and upregulates TNF-α and the pro-inflammatory receptor of the cytokine interleukin 6 (IL6). Here we propose that ACE2 contributes essentially to reverse this inflammatory state by downregulating the pro-inflammatory peptides of the angiotensin-bradykinin system, and that failure to do this, possibly induced by the degradation of ACE2 by SARS-COV-2, may underlie both severe CoViD-19 infection and its many post-infection manifestations, including the multi-inflammatory syndrome of children (MIS-C). Within this view, lower severity in children despite lower ACE2 expression may be consistent with their higher expression of the alternative angiotensin II receptor ATR2 and in general of the anti-inflammatory arm of the RAS at young age.

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Section: The Atr2 Receptorsupporting

confidence: 70%

Is Covid-19 Severity Associated With ACE2 Degradation?

Bastolla

Chambers

Abia

et al. 2022

Front. Drug Discov.

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“…In SARS-CoV-2-induced pathogenesis, the virus infects host cells through the ACE2 receptor on the respiratory epithelium. The viral invasion and downregulation of the ACE2 site promotes an increase in Ang II serum levels and, as a result, AT1R overstimulation [ 24 ]. Hospitalized patients showed a wide spectrum of manifestations including pulmonary damage such as pneumonia, airways severe damage, pulmonary edema, and ARDS, the causative mechanism of death in 70% of fatal COVID-19 cases [ 37 ].…”

Section: Angiotensin II Type I Receptor (At1r) and Covid-19mentioning

confidence: 99%

“…This phenomenon begins with the activation of the metallopeptidase ADAM domain 17 (ADAM17) by the Ang II–AT1R axis via the intracellular p38/MAPK signaling pathway. ADAM17 digests the membrane forms of epidermal growth factor family members and TNF-α generating their soluble forms, all of which stimulate the NF-κB pathway [ 24 , 37 ]. Moreover, ADAM17 operates membrane-bound IL-6Rα to the soluble form (sIL-6Rα) [ 37 ].…”

Section: Angiotensin II Type I Receptor (At1r) and Covid-19mentioning

confidence: 99%

“…The sIL-6R–IL-6 complex binds to glycoprotein 130 (gp130), expressed in most cells, and transduces intracellular signaling, followed by the activation of JAK/STAT3 and the induction of excess IL-6 [ 37 , 39 ] ( Figure 4 ). IL-6 amplifier induces chronic inflammatory diseases and the production of proinflammatory cytokines, leading to cytokine storm that characterizes the most severe forms of SARS-CoV-2 infection [ 5 , 24 , 39 ]. IL-6 is a multifunctional cytokine that transmits cell signaling, regulates immune cells, and possesses a strong proinflammatory effect, with multiple biological functions [ 41 ].…”

Section: Angiotensin II Type I Receptor (At1r) and Covid-19mentioning

confidence: 99%

“…These ARBs are now extensively used for treating cardiovascular diseases (CVDs), including heart failure, hypertension, cardiac hypertrophy, and arrhythmia [ 13 ]. ARBs block the binding of Ang II to the AT1R, thus making it available for the AT2R by turning off the vasoconstrictive, proliferative, and inflammatory effects [ 24 ]. Therefore, the significant clinical effectiveness of RAS blockers, together with their benefits for target organs, provides evidence of the continued clinical importance of RAS-targeted drug development [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases

et al. 2022

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The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin–angiotensin system (RAS) in favor of the ACE–angiotensin II (Ang II)–angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II–AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

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