Neutrophil Extracellular Traps Initiate Gallstone Formation

Muñoz, Luis E.; Boeltz, Sebastian; Bilyy, Rostyslav; Schauer, Christine; Mahajan, Aparna; Widulin, Navena; Grüneboom, Anika; Herrmann, I; Boada, Edgyda; Rauh, Manfred; Krenn, Veit; Biermann, Mona; Podolska, Malgorzata J.; Hahn, Jonas; Knopf, Jasmin; Maueröder, Christian; Paryzhak, Solomiya; Dumych, Tetiana; Zhao, Yi; Neurath, Markus F.; Hoffmann, Markus; Fuchs, Tobias A.; Leppkes, Moritz; Schett, Georg; Herrmann, Martin

doi:10.1016/j.immuni.2019.07.002

Cited by 134 publications

(166 citation statements)

References 29 publications

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“…Thus, they entrap extracellular pathogens, causing bacterial death, in a process that was first described in 2004 and termed 'NETosis' [11][12][13]. NETs are capable of binding both Gram-negative and Gram-positive bacteria, and their activities not only result in bacterial death but also prevent further spread of the infection and maintain homeostasis at the point of entry, even in unexpected body compartments [14][15][16]. NETs can also ensnare and immobilise viruses, thereby preventing viral entry into cells and spreading [17].…”

Section: Introductionmentioning

confidence: 99%

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

Söderberg

Enocsson

Skogman

et al. 2019

Cells

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Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children (N = 111) and adults (N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults (p = 0.01). NET presence was associated with higher CSF levels of CXCL1 (p < 0.001), CXCL6 (p = 0.007), CXCL8 (p = 0.003), CXCL10 (p < 0.001), MMP-9 (p = 0.002), TNF (p = 0.02), IL-6 (p < 0.001), and IL-17A (p = 0.03). NETs were associated with fever (p = 0.002) and correlated with polynuclear pleocytosis (r s = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation. supervision, C.S., D.N. and L.E.M.; project administration, J.S.; funding, D.A., B.H.S., D.N., L.E.M. and C.S.; acquisition, D.A., L.E.M., C.S. and J.S. All authors have read and agreed to the published version of the manuscript.

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Section: Introductionmentioning

confidence: 99%

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

Söderberg

Enocsson

Skogman

et al. 2019

Cells

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“…Neutrophils patrol the ocular surface and form aggNETs to wipe out dust and microorganisms . NETs participate in the initiation and growth of gallstones . We assessed the NE activity in samples from murine gall fluid (Fig.…”

Section: Resultsmentioning

confidence: 99%

Treatment with DNases rescues hidden neutrophil elastase from aggregated NETs

Podolska

Mahajan

Hahn

et al. 2019

Journal of Leukocyte Biology

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The release of neutrophil extracellular traps (NETs) is one of the weapons neutrophils have in their armory. NETs consist of extracellular chromatin fibers decorated with a plethora of cytoplasmic and granular proteins, such as the antimicrobial serine protease neutrophil elastase (NE). Because the first description of NETs as beneficial to the host, reports on their double-faced role in health and disease have considerably increased recently. On one hand, NETs reportedly trap and kill bacteria and also participate in the resolution of the acute inflammation associated with infection and with tissue damage. On the other hand, numerous negative aspects of NETs contribute to the etiopathogenesis of autoimmune disorders. Employing soluble and solid fluorescent substrates, we demonstrate the interaction of NE with aggregated NETs (aggNETs), the limitation of its enzymatic activity and the containment of the enzyme from surrounding tissues. These events prevent the spread of inflammation and tissue damage. The detection of DNase 1-dependent elevation of NE activity attests the continuous presence of patrolling neutrophils forming NETs and aggNETs even under conditions physiologic conditions.

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“…In pancreatitis, PAD4 mediates the release of NETs which cause neutrophil aggregation & occlusion of pancreatic ducts (Leppkes et al, 2016). Most recently, aggregated NETs have been implicated in the formation of gallstones (Munoz et al, 2019); Munoz et al report that macropinocytosis of small crystals results in NET release that is dependent upon both PAD4 and ROS. ROS dependent formation of aggNETs has also been reported to provide an antiinflammatory shield around necrotic neutrophil filled cores in the context of nanodiamond induced sterile inflammation .…”

Section: Discussionmentioning

confidence: 99%

“…NETs are formed as a defence mechanism to immobilize invading microorganisms but also in response to sterile triggers Papayannopoulos, 2018). In some conditions, NETs have been shown to mediate neutrophil aggregation (Leppkes et al, 2016;Munoz et al, 2019;Schauer et al, 2014).…”

Section: Neutrophils Form Large Aggregates In Omfalcs Which Are Encapmentioning

confidence: 99%

Neutrophils mediate the capture of peritoneal contaminants by fat-associated lymphoid clusters of the omentum

Jackson-Jones

Smith

Magalhaes

et al. 2019

Preprint

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The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs), which collects peritoneal contaminants and provides a first layer of immunological defence within the abdomen. Using single-cell RNA sequencing and spatial analysis of omental stromal cells, we reveal that the surface of FALCs are covered with specialised mesothelial cells, which we name FALC cover cells. We demonstrate that CXCL1 is expressed by FALC cover cells and that CXCL1 is critical for the retention and accumulation of neutrophils within FALCs during peritonitis. We show that protein arginine deiminase 4 mediates the formation of dense neutrophil aggregates, which are required for the neutralisation of particles present in the peritoneal cavity. Finally, we provide confirmatory evidence in humans with acute appendicitis, that the omentum is also a site of neutrophil recruitment and bacterial capture, and is thus an important component of the immunological defence against the propagation of peritoneal contaminants.

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Neutrophil Extracellular Traps Initiate Gallstone Formation

Cited by 134 publications

References 29 publications

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

Treatment with DNases rescues hidden neutrophil elastase from aggregated NETs

Neutrophils mediate the capture of peritoneal contaminants by fat-associated lymphoid clusters of the omentum

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