| First Author | Suire S | Year | 2019 |
| Journal | J Leukoc Biol | Volume | 106 |
| Issue | 4 | Pages | 815-822 |
| PubMed ID | 30720883 | Mgi Jnum | J:280858 |
| Mgi Id | MGI:6364747 | Doi | 10.1002/JLB.2HI0918-359RR |
| Citation | Suire S, et al. (2019) Frontline Science: TNF-alpha and GM-CSF1 priming augments the role of SOS1/2 in driving activation of Ras, PI3K-gamma, and neutrophil proinflammatory responses. J Leukoc Biol 106(4):815-822 |
| abstractText | 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-gamma, a Ras-GTP, and Gbetagamma 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/TNFalpha 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. |
