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

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 (PIP 3 ), are highly dependent on PI3K-, a Ras-GTP, and G 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-PIP 3 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/TNF priming, RasGRP4 had only a minor role in the enhanced responses. In contrast, SOS1/2 acquired a substantial role in ROS formation, PIP 3 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. safeguard, as only by prior exposure to a priming agent (chemoattractant, proinflammatory cytokine, or TLR agonist) neutrophils can maximally respond to a subsequent challenge with a ligand such as In recent years, neutrophils have been found infiltrating many types of tumors and it is becoming clearer that tumor-associated neutrophils (TANs) play a role in malignant disease. 3 Two types of TAN have been described with antagonistic affects (pro-tumor or anti-tumor), which are determined by factors expressed by the stromal cells or the tumor itself. Given the presence and important roles for TNFand GM-CSF in the tumor microenvironment and the host response to cancer, 4 it is very likely that the changes in neutrophil signaling and function induced by these ligands, and the process of priming, shape tumor progression.

Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

“…In previous reports we carried out successful ablation of floxed Sos1 alleles in mice, or cells derived thereof, through the induction of Cre recombinase with tamoxifen or 4-hydroxytamoxifen, respectively [ 11 , 13 , 14 , 16 , 17 ]. However, since tamoxifen appears to affect the viability of keratinocytes in culture even at low concentrations, we decided to test the efficiency of GFP-Adeno-Cre infection as an alternative method to accomplish Sos1 depletion in freshly isolated Sos1 KO and Sos1/2 KO primary keratinocytes.…”

“…Interestingly, adult Sos1 KO or Sos2 KO mice were perfectly viable but double Sos1/2 DKO animals died very rapidly, suggesting functional redundancy between the Sos1 and Sos2 isoforms at the level of full organismal survival and homeostasis [ 11 ]. Nevertheless, a number of reports dealing with functional analysis of different biological systems in these KO animal models support the functional prevalence of Sos1 over Sos2 in physiological processes such as cell proliferation and viability, migration, inflammation, or regulation of intracellular ROS levels [ 12 , 13 , 14 ]. Likewise, a dominant role of Sos1 has also been described in various pathological processes, including the abnormal constitutive activation of NFkB in most cancer cells [ 15 ], the development of BCR-ABL-driven leukemia, and, in particular, skin homeostasis and chemically-induced skin carcinogenesis [ 16 , 17 , 18 , 19 ].…”

Sos1 Modulates Extracellular Matrix Synthesis, Proliferation, and Migration in Fibroblasts

“…Son of Sevenless (Sos) proteins are the most widely expressed and functionally relevant family of Ras guanine nucleotide exchange factors (GEFs). There are 2 members in mammals, Sos1 (ubiquitously expressed) and Sos2 ( Suire et al, 2019 ). Sos binds to Ras promoting the release of guanosine diphosphate (GDP) and the subsequent Ras activation after binding to guanosine triphosphate (GTP) ( Quilliam et al, 2002 ).…”

Phospholipase C beta1 (PI‐PLCbeta1)/Cyclin D3/protein kinase C (PKC) alpha signaling modulation during iron‐induced oxidative stress in myelodysplastic syndromes (MDS)

“…18,19 When used as source of oxidative stress, H 2 O 2 is indeed able to induce the synthesis of Phosphatidylinositol-5-phosphate, that becomes a redox-regulated second messenger via Phosphatidylinositol-5phosphate 4-kinase, possibly affecting chromatin structure or Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 expression. 20,21 Moreover, ROS formation is associated with an accumulation of Phosphatidylinositol-(3,4,5)-trisphosphate, 22 whose function is related to Phosphatidylinositol-3-kinase, that in turn can activate an oxidant-dependent downstream signaling pathway. In fact, low concentrations of H 2 O 2 can regulate cell proliferation or induce mitogenic signaling, by inactivation of Phosphatase and tensin homolog or phosphorylation of Akt.…”