Mary Wilson
Well-known member
January 12, 2023
https://doi.org/10.1073/pnas.2213317120
Maaya Morita, Aki Yoneda, Nagisa Tokunoh, +21, and Yoshiaki Okada
Significance
Due to increased exposure to various infectious diseases, including COVID-19, there is an urgent need for novel drugs that reduce mortality from severe infectious diseases. Although current drugs can suppress pathogen reproduction, immune cell activation, and inflammatory cytokine functions, these cannot effectively reduce mortality from severe infectious diseases. In this study, we focused on the endothelial cell-specific protein Roundabout4 (Robo4) that ameliorates vascular permeability in inflammation. We demonstrated that Robo4 upregulation suppresses vascular permeability and mortality in severe infectious diseases. Moreover, we also demonstrated that small molecules which enhance Robo4 expression suppress vascular permeability and mortality. Our study thus characterizes a novel therapeutic strategy against severe infectious disease that targets vascular permeability.
Abstract
There is an urgent need to develop novel drugs to reduce the mortality from severe infectious diseases with the emergence of new pathogens, including Coronavirus disease 2019 (COVID-19). Although current drugs effectively suppress the proliferation of pathogens, immune cell activation, and inflammatory cytokine functions, they cannot completely reduce mortality from severe infections and sepsis. In this study, we focused on the endothelial cell-specific protein, Roundabout 4 (Robo4), which suppresses vascular permeability by stabilizing endothelial cells, and investigated whether enhanced Robo4 expression could be a novel therapeutic strategy against severe infectious diseases. Endothelial-specific overexpression of Robo4 suppresses vascular permeability and reduces mortality in lipopolysaccharide (LPS)-treated mice. Screening of small molecules that regulate Robo4 expression and subsequent analysis revealed that two competitive small mothers against decapentaplegic (SMAD) signaling pathways, activin receptor-like kinase 5 (ALK5)-SMAD2/3 and ALK1-SMAD1/5, positively and negatively regulate Robo4 expression, respectively. An ALK1 inhibitor was found to increase Robo4 expression in mouse lungs, suppress vascular permeability, prevent extravasation of melanoma cells, and decrease mortality in LPS-treated mice. The inhibitor suppressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced endothelial barrier disruption and decreased mortality in mice infected with SARS-CoV-2. These results indicate that enhancing Robo4 expression is an efficient strategy to suppress vascular permeability and mortality in severe infectious diseases, including COVID-19, and that small molecules that upregulate Robo4 can be potential therapeutic agents against these diseases.
https://www.pnas.org/doi/full/10.1073/pnas.2213317120
https://doi.org/10.1073/pnas.2213317120
Maaya Morita, Aki Yoneda, Nagisa Tokunoh, +21, and Yoshiaki Okada
Significance
Due to increased exposure to various infectious diseases, including COVID-19, there is an urgent need for novel drugs that reduce mortality from severe infectious diseases. Although current drugs can suppress pathogen reproduction, immune cell activation, and inflammatory cytokine functions, these cannot effectively reduce mortality from severe infectious diseases. In this study, we focused on the endothelial cell-specific protein Roundabout4 (Robo4) that ameliorates vascular permeability in inflammation. We demonstrated that Robo4 upregulation suppresses vascular permeability and mortality in severe infectious diseases. Moreover, we also demonstrated that small molecules which enhance Robo4 expression suppress vascular permeability and mortality. Our study thus characterizes a novel therapeutic strategy against severe infectious disease that targets vascular permeability.
Abstract
There is an urgent need to develop novel drugs to reduce the mortality from severe infectious diseases with the emergence of new pathogens, including Coronavirus disease 2019 (COVID-19). Although current drugs effectively suppress the proliferation of pathogens, immune cell activation, and inflammatory cytokine functions, they cannot completely reduce mortality from severe infections and sepsis. In this study, we focused on the endothelial cell-specific protein, Roundabout 4 (Robo4), which suppresses vascular permeability by stabilizing endothelial cells, and investigated whether enhanced Robo4 expression could be a novel therapeutic strategy against severe infectious diseases. Endothelial-specific overexpression of Robo4 suppresses vascular permeability and reduces mortality in lipopolysaccharide (LPS)-treated mice. Screening of small molecules that regulate Robo4 expression and subsequent analysis revealed that two competitive small mothers against decapentaplegic (SMAD) signaling pathways, activin receptor-like kinase 5 (ALK5)-SMAD2/3 and ALK1-SMAD1/5, positively and negatively regulate Robo4 expression, respectively. An ALK1 inhibitor was found to increase Robo4 expression in mouse lungs, suppress vascular permeability, prevent extravasation of melanoma cells, and decrease mortality in LPS-treated mice. The inhibitor suppressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced endothelial barrier disruption and decreased mortality in mice infected with SARS-CoV-2. These results indicate that enhancing Robo4 expression is an efficient strategy to suppress vascular permeability and mortality in severe infectious diseases, including COVID-19, and that small molecules that upregulate Robo4 can be potential therapeutic agents against these diseases.
https://www.pnas.org/doi/full/10.1073/pnas.2213317120