Background and Aims: In ulcerative colitis [UC], mucosal damage occurs in areas that are infiltrated with neutrophils.The antimicrobial function of neutrophils relies in part on the formation of extracellular web-like structures, named neutrophil extracellular traps [NETs]. The formation and/or clearance of aberrant NETs have been associated with several immune diseases. Here we investigated the role of NETs in UC-related inflammation. Methods: The expression of NET-associated proteins was evaluated in colonic biopsies of patients with Crohn's disease [CD], UC and in normal controls [NC] byWestern blotting, immunofluorescence and immunohistochemistry. Colonic biopsies of UC patients were analysed before and after anti-tumour necrosis factor α [anti-TNF-α] treatment.The capacity of neutrophils to produce NETs upon activation was tested in vitro. UC lamina propria mononuclear cells [LPMCs] were cultured with NETs in the presence or absence of an extracellular signal-regulated kinase-1/2 [ERK1/2] inhibitor and inflammatory cytokine induction was assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We also characterized the contribution of NETs in dextran sodium sulfate [DSS]-induced colitis. Results: NET-associated proteins were over-expressed in inflamed colon of UC patients as compared to CD patients and NC. Circulating neutrophils of UC patients produced NETs in response to TNF-α stimulation, and reduced expression of NET-related proteins and diminished NET formation were seen in patients receiving successful treatment with anti-TNF-α.Treatment of UC LPMCs with NETs activated ERK1/2, thus enhancingTNF-α and interleukin-1β [IL-1β] production. NETs were induced in mice with DSS-colitis and in vivo inhibition of NET release attenuated colitis. Conclusions: Our data show that NET release occurs in UC and suggest a role for NETs in sustaining mucosal inflammation in this disorder.

Neutrophil extracellulartraps sustain inflammatory signals in ulcerative colitis

Figliuzzi M. M.;Monteleone G.
2019-01-01

Abstract

Background and Aims: In ulcerative colitis [UC], mucosal damage occurs in areas that are infiltrated with neutrophils.The antimicrobial function of neutrophils relies in part on the formation of extracellular web-like structures, named neutrophil extracellular traps [NETs]. The formation and/or clearance of aberrant NETs have been associated with several immune diseases. Here we investigated the role of NETs in UC-related inflammation. Methods: The expression of NET-associated proteins was evaluated in colonic biopsies of patients with Crohn's disease [CD], UC and in normal controls [NC] byWestern blotting, immunofluorescence and immunohistochemistry. Colonic biopsies of UC patients were analysed before and after anti-tumour necrosis factor α [anti-TNF-α] treatment.The capacity of neutrophils to produce NETs upon activation was tested in vitro. UC lamina propria mononuclear cells [LPMCs] were cultured with NETs in the presence or absence of an extracellular signal-regulated kinase-1/2 [ERK1/2] inhibitor and inflammatory cytokine induction was assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We also characterized the contribution of NETs in dextran sodium sulfate [DSS]-induced colitis. Results: NET-associated proteins were over-expressed in inflamed colon of UC patients as compared to CD patients and NC. Circulating neutrophils of UC patients produced NETs in response to TNF-α stimulation, and reduced expression of NET-related proteins and diminished NET formation were seen in patients receiving successful treatment with anti-TNF-α.Treatment of UC LPMCs with NETs activated ERK1/2, thus enhancingTNF-α and interleukin-1β [IL-1β] production. NETs were induced in mice with DSS-colitis and in vivo inhibition of NET release attenuated colitis. Conclusions: Our data show that NET release occurs in UC and suggest a role for NETs in sustaining mucosal inflammation in this disorder.
2019
Inflammatory bowel disease
NETosis
Neutrophils
PAD4
Ulcerative colitis
Animals
Colitis, Ulcerative
Colon
Disease Models, Animal
Extracellular Traps
Female
Fluorescent Antibody Technique
Humans
Inflammation
Interleukin-1beta
Intestinal Mucosa
MAP Kinase Signaling System
Mice
Mice, Inbred BALB C
Real-Time Polymerase Chain Reaction
Tumor Necrosis Factor-alpha
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12317/64154
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