Interleukin-1RA Mitigates SARS-CoV-2-Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice

Objective: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood. Approach and Results: We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3 (NLR family pyrin domain containing 3)-caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1 beta, and downregulation of the lung endothelial adherens junction protein VE (vascular endothelial)-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post-SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival. Conclusions: These results provide insights into the central role of NLRP3-caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19).

Automated summary

The research demonstrates that SARS-CoV-2 infection activates inflammatory signaling pathways and causes lung vascular injury and edema formation in infected mice and human lung microvascular endothelial cells. Selective blockade of IL-1 receptor signaling prevents lung vascular injury and edema, improving survival rates in COVID-19 patients.