Journal
GUT
Volume 71, Issue 12, Pages 2414-2429Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2021-324725
Keywords
IBD; mucosal injury; leukocytes; ulcerative colitis; bleeding
Categories
Funding
- Deutsche Forschungsgemeinschaft [BE3686/2-1, KFO 257 CEDER, FOR 2438, TRR241, CRC 1181, SPP1656, SCHA 2040/1-1]
- German Bundeswirtschaftsministerium [ZF4010106MD9]
- Interdisciplinary Center for Clinical Research (IZKF) of the University Erlangen-Nuremberg
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Bleeding ulcers and erosions are common in active ulcerative colitis, with fibrin layers correlated with rectal bleeding. Neutrophils induce secondary immunothrombosis through PAD4-dependent mechanisms, protecting against acute colitis and rectal bleeding. Deficiency in immunothrombosis can lead to exacerbated colitis and increased bleeding.
Objective Bleeding ulcers and erosions are hallmarks of active ulcerative colitis (UC). However, the mechanisms controlling bleeding and mucosal haemostasis remain elusive. Design We 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. Results Erosions 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. Conclusion Our findings uncover that neutrophils induce secondary immunothrombosis by PAD4-dependent mechanisms. Insufficient immunothrombosis may favour rectal bleeding in UC.
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