Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis

Yu, Changhui; Merza, Mohammed; Luo, Lingtao; Thorlacius, Henrik

doi:10.1016/j.ejphar.2014.11.020

Cited by 17 publications

(12 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results build on work published by other labs identifying roles for a Ras‐sensitive‐network controlling important neutrophil functions such as ROS formation, NET release, and tissue infiltration (in acute pancreatitis) and in disease processes, such as autoimmune vasculitis (via antineutrophil cytoplasmic antibodies—ANCA). Our results provide a molecular framework with which to understand how Ras signaling orchestrates ROS formation in basal and primed neutrophils.…”

Section: Discussionsupporting

confidence: 74%

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

Suire

Baltanás

Segonds‐Pichon

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 74%

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

Suire

Baltanás

Segonds‐Pichon

et al. 2019

Journal of Leukocyte Biology

View full text Add to dashboard Cite

show abstract

“…In the 2 years following the publication of the study ‘Treatment with Evasin‐3 abrogates neutrophil‐mediated inflammation in mouse acute pancreatitis’ , two studies confirmed our results about the chemokine upregulation in mouse models of acute pancreatitis . Specifically, Merza and co‐workers observed a 20‐fold increase of CXCL2, whereas data from Yu et al .…”

Section: Treatment With Evasin‐3 Abrogates Neutrophil‐mediated Inflamsupporting

confidence: 81%

“…Treatment with Evasin-3 abrogates neutrophilmediated inflammation in mouse acute pancreatitis [113] (Federico Carbone and Fabrizio Montecucco) In the 2 years following the publication of the study 'Treatment with Evasin-3 abrogates neutrophil-mediated inflammation in mouse acute pancreatitis' [113], two studies confirmed our results about the chemokine upregulation in mouse models of acute pancreatitis [114,115]. Specifically, Merza and co-workers observed a 20-fold increase of CXCL2, whereas data from Yu et al showed a rise of serum CXCL1 and CXCL2 in the pancreatic tissue by threefold and eightfold, respectively.…”

Section: And Jussi Sipil€ A)supporting

confidence: 72%

Research update for articles published in EJCI in 2014

Arellano-Orden

Bacopoulou

Băicuș

et al. 2016

Eur J Clin Investigation

View full text Add to dashboard Cite

show abstract

“…40,41 Indeed, during acute pancreatitis, migration of neutrophils into the pancreatic tissue is amplified. 12,[42][43][44] Migration involves several adhesion molecules expressed on the neutrophil surface, such as Mac-1, CD62L, or LFA-1. 45,46 Pancreatic leukostasis is also dependent on the activity of the endothelium, which, during exacerbated inflammation, expresses intercellular adhesion molecule 1 and junction adhesion molecule C on its surface, which can then bind to neutrophils and cause them to transmigrate.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, such an inflammatory response is observed in other pathologies, notably during pancreatitis . Indeed, during acute pancreatitis, migration of neutrophils into the pancreatic tissue is amplified . Migration involves several adhesion molecules expressed on the neutrophil surface, such as Mac‐1, CD62L, or LFA‐1 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the CD40/CD40L complex protects mice against ALI‐induced pancreas degradation

et al. 2019

View full text Add to dashboard Cite

BACKGROUND Acute lung injury (ALI) is a severe complication of transfusion. In a previous study, we saw that inhibition of the CD40/CD40L complex allowed restoration of ALI lesions in an experimental mouse model. OBJECTIVES This study focused on pancreas‐associated injury development during experimental ALI pathogenesis and its limitation through CD40/CD40L complex inhibition. MATERIALS AND METHODS An ALI mouse model was established through intraperitoneal lipopolysaccharide and intravenous anti–major histocompatibility complex class I monoclonal antibody injection. Preemption of lesions was achieved with intravenous injection of neutralizing anti‐CD40L monoclonal antibody 30 minutes before the trigger, that is, anti–major histocompatibility complex class I monoclonal antibody administration. Histology and immunoassay analyses were used to evaluate pancreatic lesions. RESULTS ALI development induced significant degradation of the lungs and pancreas and was associated with pancreatic lesions. Different scores were established showing more severe injury to the pancreas in ALI conditions; however, injury was significantly reduced through CD40/CD40L complex inhibition. CONCLUSION This study supports the idea that several organs are exposed during ALI development, and particularly when such experimental ALI aims at mimicking transfusion‐associated ALI; nevertheless, preventive treatment inhibiting CD40/CD40L (sCD40L) complex formation provides protection from lung disease as well as disease of other organs.

show abstract

Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis

Cited by 17 publications

References 35 publications

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

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

Research update for articles published in EJCI in 2014

Inhibition of the CD40/CD40L complex protects mice against ALI‐induced pancreas degradation

Contact Info

Product

Resources

About