Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis

Dinallo, Vincenzo; Marafini, Irene; Fusco, Davide Di; Laudisi, Federica; Franzè, Eleonora; Grazia, Antonio Di; Figliuzzi, Michele Mario; Caprioli, Flavio; Stolfi, Carmine; Monteleone, Ivan; Monteleone, Giovanni

doi:10.1093/ecco-jcc/jjy215

Cited by 163 publications

(163 citation statements)

References 54 publications

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“…Although NET components play an antimicrobial role, excessive NET formation tends to induce a proinflammatory state and contributes to host cell injury [ 10 ]. Indeed, abundant NET-associated proteins and NET structures have been detected by proteomics and confocal microscopy analysis in intestinal biopsies from individuals with CD [ 11 ] and UC [ 12 , 13 , 14 ]. Furthermore, several NET-associated proteins, such as calprotectin and myeloperoxidase (MPO), are documented IBD biomarkers [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, several NET-associated proteins, such as calprotectin and myeloperoxidase (MPO), are documented IBD biomarkers [ 15 ]. Furthermore, NETs amplify the inflammatory signals in UC and promote a hypercoagulable state in IBD, indicating their involvement in the pathogenesis of IBD [ 14 , 16 ]. However, the mechanisms by which NETs modulate intestinal barrier integrity and the progression of gut inflammation remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

et al. 2020

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Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

et al. 2020

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“…Second, MFG-E8 inhibits active NLRP3 inflammasomeprimed NETs formation in diabetes. In diabetic conditions, neutrophils produce more superoxide and cytokines than normoglycemic conditions 8,27,28 . IL-1β and IL-18 can attract neutrophils, and also prime recruited neutrophils to NETosis, releasing NETs in damaged tissues 13,14,29 .…”

Section: Discussionmentioning

confidence: 99%

“…Under diabetic conditions, reactive oxygen species, cytokines also induced NET formation 6 . TNF-α stimulates neutrophils to NETosis, which is elevated in diabetic patients 7,8 . NETosis begins with the activation of peptidylarginine deiminase 4 (PAD4), an enzyme leads to histone citrullination and chromatin decondensation 9 .…”

Section: Introductionmentioning

confidence: 99%

MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis

et al. 2020

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Sustained activation of NLRP3 inflammasome and release of neutrophil extracellular traps (NETs) impair wound healing of diabetic foot ulcers (DFUs). Our previous study reported that milk fat globule epidermal growth factor VIII (MFG-E8) attenuates tissue damage in systemic lupus erythematosus. However, the functional effect of MFG-E8 on “NLRP3 inflammasome-NETs” inflammatory loop in wound healing of diabetes is not completely elucidated. In this study, neutrophils from DFU patients are susceptible to undergo NETosis, releasing more NETs. The circulating levels of NET components neutrophil elastase and proteinase 3 and inflammatory cytokines IL-1β and IL-18 were significantly elevated in DFU patients compared with healthy controls or diabetic patients, in spite of higher levels of MFG-E8 in DFU patients. In Mfge8−/− diabetic mice, skin wound displayed exaggerated inflammatory response, including leukocyte infiltration, excessive activation of NLRP3 inflammasome (release of higher IL-1β, IL-18, and TNF-α), largely lodged NETs, resulting in poor angiogenesis and wound closure. When stimulated with high-dose glucose or IL-18, MFG-E8-deficient neutrophils release more NETs than WT neutrophils. After administration of recombinant MFG-E8, IL-18-primed NETosis of WT or Mfge8−/− neutrophils was significantly inhibited. Furthermore, NET and mCRAMP (component of NETs, the murine equivalent of cathelicidin LL-37 in human)-mediated activation of NLRP3 inflammasome and production of IL-1β/IL-18 were significantly elevated in Mfge8−/− macrophages compared with WT macrophages, which were also significantly dampened by the administration of rmMFG-E8. Therefore, our study demonstrated that as inhibitor of the “NLRP3 inflammasome-NETs” inflammatory loop, exogenous rMFG-E8 improves angiogenesis and accelerates wound healing, highlighting possible therapeutic potential for DFUs.

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“…They have been evaluated in neonates with necrotizing enterocolitis and showed a significant correlation with intestinal inflammation and disease severity 19 . Moreover, NETs have been directly linked with inflammatory bowel disease (IBD) in adult and pediatric patients 40,41 . However, they have not been evaluated as systemic biomarkers in these patients.…”

Section: Discussionmentioning

confidence: 99%

Markers of neutrophil activation and extracellular traps formation are predictive of appendicitis in mice and humans: a pilot study

Boettcher

Esser

Trah

et al. 2020

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Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune defense against bacterial infections, and appendicitis is considered an inflammation reaction of the appendix, we hypothesized that neutrophil activation and NET formation play an essential role in appendicitis development and maintenance. Therefore, this pilot study aimed to establish a murine model of appendicitis and to evaluate ETs markers to diagnose appendicitis in mice and humans. The study used 20 (12 appendicitis- and 8 controls) 6-week old mice which underwent advanced appendicitis induction using a modified caecal ligation puncture procedure. During the study, cell-free DNA, neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated Histone H3 (H3cit) were assessed. Additionally, samples of 5 children with histologically confirmed appendicitis and 5 matched controls with catarrhal appendicitis, were examined for the same biomarkers. Moreover, NE, MPO, and H3cit were assessed histologically via immunofluorescence in mice and humans. All mice in the appendicitis group developed an advanced form of appendicitis with focal peritonitis. In mice and humans with appendicitis, markers of neutrophil activation and ETs formation (especially cfDNA, NE and H3cit) were significantly elevated in blood and tissue compared to controls. Ultimately, biomarkers correlated extremely well with tissue expression and thus disease severity. It appears that neutrophil activation and possibly NETs contribute to appendicitis development and biomarkers of neutrophil activation and ET formation reflect disease severity and thus could be used as biomarkers for appendicitis. However, large prospective clinical studies are needed to confirm our findings.

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Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis

Cited by 163 publications

References 54 publications

Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

MFG-E8 accelerates wound healing in diabetes by regulating “NLRP3 inflammasome-neutrophil extracellular traps” axis

Markers of neutrophil activation and extracellular traps formation are predictive of appendicitis in mice and humans: a pilot study

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