Frontline Science: TNF-α and GM-CSF1 priming augments the role of SOS1/2 in driving activation of Ras, PI3K-γ, and neutrophil proinflammatory responses.
J Leukoc Biol
; 106(4): 815-822, 2019 10.
Article
en En
| MEDLINE
| ID: mdl-30720883
ABSTRACT
Circulating neutrophils are, by necessity, quiescent and relatively unresponsive to acute stimuli. In regions of inflammation, mediators can prime neutrophils to react to acute stimuli with stronger proinflammatory, pathogen-killing responses. In neutrophils G protein-coupled receptor (GPCR)-driven proinflammatory responses, such as reactive oxygen species (ROS) formation and accumulation of the key intracellular messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ), are highly dependent on PI3K-γ, a Ras-GTP, and Gßγ coincidence detector. In unprimed cells, the major GPCR-triggered activator of Ras is the Ras guanine nucleotide exchange factor (GEF), Ras guanine nucleotide releasing protein 4 (RasGRP4). Although priming is known to increase GPCR-PIP3 signaling, the mechanisms underlying this augmentation remain unclear. We used genetically modified mice to address the role of the 2 RasGEFs, RasGRP4 and son of sevenless (SOS)1/2, in neutrophil priming. We found that following GM-CSF/TNFα priming, RasGRP4 had only a minor role in the enhanced responses. In contrast, SOS1/2 acquired a substantial role in ROS formation, PIP3 accumulation, and ERK activation in primed cells. These results suggest that SOS1/2 signaling plays a key role in determining the responsiveness of neutrophils in regions of inflammation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor Estimulante de Colonias de Granulocitos y Macrófagos
/
Factor de Necrosis Tumoral alfa
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Proteínas ras
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Fosfatidilinositol 3-Quinasas
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Proteínas Son Of Sevenless
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Proteína SOS1
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Inflamación
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Neutrófilos
Límite:
Animals
Idioma:
En
Revista:
J Leukoc Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido