COVID-19 and pneumonia: a role for the uPA/uPAR system

Abstract

Here, we highlight recent findings on the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system that suggest its potential role as a main orchestrator of fatal progression to pulmonary, kidney, and heart failure in patients with coronavirus. Patients with prolonged background inflammation can present aberrant inflammatory reactions, well recognized as the main factors that can result in death and probably sustained by a dysregulated uPA/uPAR system. SuPAR, the soluble form of uPAR, represents a biomarker of disease progression, and its levels correlate well with comorbidities associated with the death of patients with coronavirus. New drugs that regulate the uPA/uPAR system could help treat the severe complications of highly pathogenic human coronaviruses (hCoVs), including pandemic coronavirus 2019 (COVID-19).

Figure 1

Box plot describing soluble urokinase plasminogen activator (suPAR) levels in healthy controls and patients, asdetailed in Table 1 in the main text.

Figure 2

Hypothetical model of urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system function. Upon binding to uPAR, uPA catalyzes the conversion of plasminogen into plasmin, a serine protease involved in extracellular matrix (ECM) degradation and cell motility. Plasminogen activator-inhibitor 1 (PAI-1) is a negative regulator of the plasminergic system . Upon uPA binding to uPAR, a conformational transition occurs, and the uPAR^88–92 sequence is exposed and can participate in binding with lateral co-receptors. In addition, chymotrypsin and cathepsin G hydrolyze uPAR at the D-I:D-II linker region, giving rise to a truncated D-II D-III GPI-anchored uPAR and to the peptide fragment S⁸⁸RSRY⁹². Furthermore, uPAR can be detached from the GPI anchor, leading to the full or truncated soluble (su)PAR form. Beside its upstream role in fibrinolysis, uPAR lacking an intracellular domain forms supramolecular complexes by interacting with transmembrane receptors: formyl peptide receptors (FPRs), integrins (mainly, αvβ3 integrin), and vascular endothelial growth factor receptor 2 (VEGFR-2). FPR can also be activated by the peptide fragment S⁸⁸RSRY⁹², and formylated mitochondrial or bacterial peptides. VEGFR-2 can also be activated by VEGF-A. The activation of these co-receptors subsequently produces intracellular signaling that ends with the synthesis of proangiogenesis and proinflammatory mediators. The uPA/uPAR system is also represented on the cell surface , , . UPARANT binds with very high affinity to FPR1 and with lower affinity to αvβ3 integrin, and antagonizes uPAR co-receptor activation, affecting the plasminergic system and fibrinolysis. Abbreviations: CREB, cAMP response element-binding protein; FAK, focal adhesion kinase; HIF-1, hypoxia inducible factor 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Src, proto-oncogene tyrosine-protein kinase; STAT-3, signal transducer and activator of transcription 3.