tetano
Editor, Senior Moderator
Arterioscler Thromb Vasc Biol
. 2021 Sep 9;ATVBAHA121316925.
doi: 10.1161/ATVBAHA.121.316925. Online ahead of print.
Interleukin-1RA Mitigates SARS-CoV-2-Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice
Shiqin Xiong[SUP] 1 2 [/SUP], Lianghui Zhang[SUP] 1 [/SUP], Justin M Richner[SUP] 3 [/SUP], Jake Class[SUP] 1 3 [/SUP], Jalees Rehman[SUP] 4 [/SUP], Asrar B Malik[SUP] 1 [/SUP]
Affiliations
Abstract
Objective: SARS-CoV-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-caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE-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).
Keywords: SARS-CoV-2; edema; interleukin-1; pyroptosis; vascular system injuries.
. 2021 Sep 9;ATVBAHA121316925.
doi: 10.1161/ATVBAHA.121.316925. Online ahead of print.
Interleukin-1RA Mitigates SARS-CoV-2-Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice
Shiqin Xiong[SUP] 1 2 [/SUP], Lianghui Zhang[SUP] 1 [/SUP], Justin M Richner[SUP] 3 [/SUP], Jake Class[SUP] 1 3 [/SUP], Jalees Rehman[SUP] 4 [/SUP], Asrar B Malik[SUP] 1 [/SUP]
Affiliations
- PMID: 34496633
- DOI: 10.1161/ATVBAHA.121.316925
Abstract
Objective: SARS-CoV-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-caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE-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).
Keywords: SARS-CoV-2; edema; interleukin-1; pyroptosis; vascular system injuries.