Administration of a CXC Chemokine Receptor 2 (CXCR2) Antagonist, SCH527123, Together with Oseltamivir Suppresses NETosis and Protects Mice from Lethal Influenza and Piglets from Swine-Influenza Infection
| Autor: | Narasaraju Teluguakula, Mallika Achanta, Jennifer M. Rudd, Timothy A. Snider, Prasanthi Maram, Vincent T. K. Chow, Sivasami Pulavendran, Harshini K. Ashar, Jerry R. Malayer |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oseltamivir Neutrophils Swine Stimulation Extracellular Traps Neutrophil Activation Receptors Interleukin-8B Pathology and Forensic Medicine Mice 03 medical and health sciences Chemokine receptor chemistry.chemical_compound 0302 clinical medicine Orthomyxoviridae Infections Influenza Human Extracellular Animals Humans Medicine CXC chemokine receptors Lung biology business.industry Antagonist Regular Article Neutrophil extracellular traps respiratory tract diseases 030104 developmental biology chemistry 030220 oncology & carcinogenesis Neutrophil elastase Benzamides Immunology biology.protein Leukocyte Elastase business Cyclobutanes |
| Zdroj: | Am J Pathol |
| ISSN: | 0002-9440 |
| Popis: | Excessive neutrophil influx, their released neutrophil extracellular traps (NETs), and extracellular histones are associated with disease severity in influenza-infected patients. Neutrophil chemokine receptor CXC chemokine receptor 2 (CXCR2) is a critical target for suppressing neutrophilic inflammation. Herein, temporal dynamics of neutrophil activity and NETosis were investigated to determine the optimal timing of treatment with the CXCR2 antagonist, SCH527123 (2-hydroxy-N,N-dimethyl-3-[2-([(R)-1-(5-methyl-furan-2-yl)-propyl]amino)-3,4-dioxo-cyclobut-1-enylamino]-benzamide), and its efficacy together with antiviral agent, oseltamivir, was tested in murine and piglet influenza-pneumonia models. SCH527123 plus oseltamivir markedly improved survival of mice infected with lethal influenza, and diminished lung pathology in swine-influenza-infected piglets. Mechanistically, addition of SCH527123 in the combination treatment attenuated neutrophil influx, NETosis, in both mice and piglets. Furthermore, neutrophils isolated from influenza-infected mice showed greater susceptibility to NETotic death when stimulated with a CXCR2 ligand, IL-8. In addition, CXCR2 stimulation induced nuclear translocation of neutrophil elastase, and enhanced citrullination of histones that triggers chromatin decondensation during NET formation. Studies on temporal dynamics of neutrophils and NETs during influenza thus provide important insights into the optimal timing of CXCR2 antagonist treatment for attenuating neutrophil-mediated lung pathology. These findings reveal that pharmacologic treatment with CXCR2 antagonist together with an antiviral agent could significantly ameliorate morbidity and mortality in virulent and sublethal influenza infections. |
| Databáze: | OpenAIRE |
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