RT Journal Article
SR Electronic
T1 Neutrophils prevent rectal bleeding in ulcerative colitis by peptidyl-arginine deiminase-4-dependent immunothrombosis
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 2414
OP 2429
DO 10.1136/gutjnl-2021-324725
VO 71
IS 12
A1 Leppkes, Moritz
A1 Lindemann, Aylin
A1 Gößwein, Stefanie
A1 Paulus, Susanne
A1 Roth, Dominik
A1 Hartung, Anne
A1 Liebing, Eva
A1 Zundler, Sebastian
A1 Gonzalez-Acera, Miguel
A1 Patankar, Jay V
A1 Mascia, Fabrizio
A1 Scheibe, Kristina
A1 Hoffmann, Markus
A1 Uderhardt, Stefan
A1 Schauer, Christine
A1 Foersch, Sebastian
A1 Neufert, Clemens
A1 Vieth, Michael
A1 Schett, Georg
A1 Atreya, Raja
A1 Kühl, Anja A
A1 Bleich, Andre
A1 Becker, Christoph
A1 Herrmann, Martin
A1 Neurath, Markus F
YR 2022
UL http://gut.bmj.com/content/71/12/2414.abstract
AB 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.Data are available in a public, open access repository. Data sharing not applicable as no datasets generated and/or analysed for this study. Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.RNAseq studies are made available in a public, open access repository (Accession: E-MTAB-10824). Additional data are available upon reasonable request.