Neutrophil extracellular traps-associated protein peptidyl arginine deaminase 4 immunohistochemical expression in ulcerative colitis and its association with the prognostic predictors

hafez, Amal Abd El; Mohamed, Abdelaty Shawky; Shehta, Ahmed; Sheta, Heba

doi:10.1016/j.prp.2020.153102

Cited by 21 publications

(12 citation statements)

References 25 publications

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“…We identified extracellular chromatin, aggregated neutrophils and PAD4 activity in immunothrombi, which cover mucosal ulcerations and erosions in UC. Erosions, ulcerations, blood, neutrophils and fibrin are positively associated with severe disease 32 33. However, we observed that blood/haematin coverage of erosions rather than fibrin coverage is associated with rectal bleeding, consistent with the role of fibrin as a protective emergency barrier.…”

Section: Discussionsupporting

confidence: 68%

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis

Leppkes

Lindemann

Gößwein

et al. 2021

Gut

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ObjectiveBleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive.DesignWe used high-resolution endoscopy and colon tissue samples of active UC (n = 36) as well as experimental models of physical and chemical mucosal damage in mice deficient for peptidyl-arginine deiminase-4 (PAD4), gnotobiotic mice and controls. We employed endoscopy, histochemistry, live-cell microscopy and flow cytometry to study eroded mucosal surfaces during mucosal haemostasis.ResultsErosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Transcriptome analyses showed significantly elevated PAD4 expression in active UC. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding.ConclusionOur findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.

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Section: Discussionsupporting

confidence: 68%

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis

Leppkes

Lindemann

Gößwein

et al. 2021

Gut

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“…It suggests that a positive regulatory relationship exists between TNF-α and NETs in UC patients and TNF-α spurs the forming of NETs, and NETs in turn boosts the secretion of TNF-α. In another report, the researchers initially analyzed neutrophils in peripheral blood and colon tissue of 48 patients with IBD and showed that patients with active disease exhibited more NETs release than those with inactive lesions [ 116 ]. Likewise, Angelidou et al .…”

Section: Nets and Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

“…The degradation of NETs reduces colitis and prevents increased expression of pro-inflammatory factors as well as neoplasia and thrombosis relevant to IBD [ 115 , 120 ]. In terms of thrombosis, NETs release phosphatidylserine (PS) by being prone to a prothrombotic state, and LPS activates TLR2 and TLR4 in platelets and endothelial cells, thereby inducing pro-coagulant properties and leading to thrombosis [ 116 ].…”

Section: Nets and Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

The emerging role of neutrophilic extracellular traps in intestinal disease

et al. 2022

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Neutrophil extracellular traps (NETs) are extracellular reticular fibrillar structures composed of DNA, histones, granulins and cytoplasmic proteins that are delivered externally by neutrophils in response to stimulation with various types of microorganisms, cytokines and host molecules, etc. NET formation has been extensively demonstrated to trap, immobilize, inactivate and kill invading microorganisms and acts as a form of innate response against pathogenic invasion. However, NETs are a double-edged sword. In the event of imbalance between NET formation and clearance, excessive NETs not only directly inflict tissue lesions, but also recruit pro-inflammatory cells or proteins that promote the release of inflammatory factors and magnify the inflammatory response further, driving the progression of many human diseases. The deleterious effects of excessive release of NETs on gut diseases are particularly crucial as NETs are more likely to be disrupted by neutrophils infiltrating the intestinal epithelium during intestinal disorders, leading to intestinal injury, and in addition, NETs and their relevant molecules are capable of directly triggering the death of intestinal epithelial cells. Within this context, a large number of NETs have been reported in several intestinal diseases, including intestinal infections, inflammatory bowel disease, intestinal ischemia–reperfusion injury, sepsis, necrotizing enterocolitis, and colorectal cancer. Therefore, the formation of NET would have to be strictly monitored to prevent their mediated tissue damage. In this review, we summarize the latest knowledge on the formation mechanisms of NETs and their pathophysiological roles in a variety of intestinal diseases, with the aim of providing an essential directional guidance and theoretical basis for clinical interventions in the exploration of mechanisms underlying NETs and targeted therapies.

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“…This increase is associated with the release of TNF-α and the presence of lipopolysaccharides, two factors that contribute to neutrophil activation. Other factors that can contribute to NETs production are IL-8 produced by endothelial cells, and an increased abundance of protein arginine deiminase 4 (PAD4) [ 30 , 31 , 43 ]. PAD4 is more abundant in intestinal tissue from UC patients than healthy individuals [ 31 ], and in damaged tissue rather than healthy tissue from the same individual [ 30 , 31 , 32 ].…”

Section: Ibd Pathophysiologymentioning

confidence: 99%

Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

Saéz

Herrero‐Fernández

Gómez-Bris

et al. 2023

IJMS

133

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Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.

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Neutrophil extracellular traps-associated protein peptidyl arginine deaminase 4 immunohistochemical expression in ulcerative colitis and its association with the prognostic predictors

Cited by 21 publications

References 25 publications

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis

Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis

The emerging role of neutrophilic extracellular traps in intestinal disease

Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

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