1. R406 reduces lipopolysaccharide-induced neutrophil activation.
- Author
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Warner S, Teague HL, Ramos-Benitez MJ, Panicker S, Allen K, Gaihre S, Moyer T, Parachalil Gopalan B, Douagi I, Shet A, Kanthi Y, Suffredini AF, Chertow DS, and Strich JR
- Subjects
- Humans, Pyridines pharmacology, Syk Kinase metabolism, Reactive Oxygen Species metabolism, Extracellular Traps immunology, Extracellular Traps drug effects, Extracellular Traps metabolism, Phagocytosis drug effects, Morpholines pharmacology, Interleukin-8 metabolism, Pyrimidines pharmacology, SARS-CoV-2 immunology, COVID-19 immunology, Cell Degranulation drug effects, Sepsis immunology, Sepsis drug therapy, Receptors, IgG metabolism, Receptors, IgG immunology, Imidazoles pharmacology, Cell Adhesion drug effects, Lipopolysaccharides pharmacology, Lipopolysaccharides immunology, Neutrophils immunology, Neutrophils drug effects, Neutrophils metabolism, Neutrophil Activation drug effects, Aminopyridines pharmacology
- Abstract
Modulating SYK has been demonstrated to have impacts on pathogenic neutrophil responses in COVID-19. During sepsis, neutrophils are vital in early bacterial clearance but also contribute to the dysregulated immune response and organ injury when hyperactivated. Here, we evaluated the impact of R406, the active metabolite of fostamatinib, on neutrophils stimulated by LPS. We demonstrate that R406 was able to effectively inhibit NETosis, degranulation, ROS generation, neutrophil adhesion, and the formation of CD16
low neutrophils that have been linked to detrimental outcomes in severe sepsis. Further, the neutrophils remain metabolically active, capable of releasing cytokines, perform phagocytosis, and migrate in response to IL-8. Taken together, this data provides evidence of the potential efficacy of utilizing fostamatinib in bacterial sepsis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)- Published
- 2024
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