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Published on: May 31, 2018
R406 reduces lipopolysaccharide-induced neutrophil activation
Seth Warner1, Heather L Teague1, Marcos J Ramos-Benitez2
1Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA; Critical Care Medicine Department, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA.
R406, fostamatinib's active metabolite, effectively inhibits harmful neutrophil responses in sepsis models. This suggests fostamatinib may be a promising treatment for bacterial sepsis by controlling neutrophil hyperactivation.
Area of Science:
- Immunology
- Pharmacology
Background:
- Neutrophils play a dual role in sepsis, aiding bacterial clearance but also causing organ damage when hyperactivated.
- Modulating spleen tyrosine kinase (SYK) impacts pathogenic neutrophil responses, as seen in COVID-19.
Purpose of the Study:
- To evaluate the impact of R406, the active metabolite of fostamatinib, on lipopolysaccharide (LPS)-stimulated neutrophils.
- To assess R406's potential in mitigating detrimental neutrophil functions during bacterial sepsis.
Main Methods:
- Neutrophils were stimulated with LPS in the presence of R406.
- Assays were performed to measure NETosis, degranulation, reactive oxygen species (ROS) generation, and neutrophil adhesion.
Main Results:
- R406 significantly inhibited NETosis, degranulation, ROS generation, and neutrophil adhesion.
- R406 prevented the formation of CD16low neutrophils associated with severe sepsis outcomes.
- Neutrophils treated with R406 retained metabolic activity, cytokine release, phagocytosis, and IL-8-induced migration.
Conclusions:
- R406 effectively modulates key neutrophil functions implicated in sepsis pathogenesis.
- Fostamatinib demonstrates potential as a therapeutic agent for bacterial sepsis by targeting aberrant neutrophil responses.
