Neutrophil Extracellular Traps Induce Intestinal Damage and Thrombotic Tendency in Inflammatory Bowel Disease

Abstract

Background and Aims Despite the presence of neutrophil extracellular traps [NETs] in inflamed colon having been confirmed, the role of NETs, especially the circulating NETs, in the progression and thrombotic tendency of inflammatory bowel disease [IBD] remains elusive. We extended our previous study to prove that NETs constitute a central component in the progression and prothrombotic state of IBD. Methods In all 48 consecutive patients with IBD were studied. Acute colitis was induced by the treatment of C57BL/6 mice with 3.5% dextran sulphate sodium [DSS] in drinking water for 6 days. Peripheral blood neutrophils and sera were collected from IBD patients and murine colitis models. Exposed phosphatidylserine [PS] was analysed with flow cytometry and confocal microscopy. Procoagulant activity was evaluated using clotting time, purified coagulation complex, and fibrin formation assays. Results We observed higher plasma NET levels and presence of NETs in colon tissue in patients with active IBD. More importantly, NETs were induced in mice with DSS colitis, and inhibition of NET release attenuated colitis as well as colitis-associated tumorigenesis. NET degradation through DNase administration decreased cytokine levels during DSS-induced colitis. In addition, DNase treatment also significantly attenuated the accelerated thrombus formation and platelet activation observed in DSS-induced colitis. NETs triggered PS-positive microparticle release and PS exposure on platelets and endothelial cells partially through TLR2 and TLR4, converting them to a procoagulant phenotype. Conclusions NETs exacerbate colon tissue damage and drive thrombotic tendency during active IBD. Strategies directed against NET formation may offer a potential therapeutic approach for the treatment of IBD.

Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis

“…To determine whether NET production is increased in the colon during colitis, we utilized a mouse model of DSS-induced colitis, which shares many similarities with human UC [ 23 ]. Although we did not detect the presence of MPO-DNA complexes in the plasma that was reported in mice received 3.5% DSS for 6 d ( Supplemental Figure S1 ) [ 24 ], colonic homogenates of mice with 2.5% DSS-induced colitis contained significantly more MPO-DNA complexes than colonic homogenates of the control mice ( Figure 1 A). We next characterized NETs in the colon sections of the control and DSS mice.…”

“…Accordingly, an elevated abundance of neutrophil- and NET-associated components has been recently shown in both CD [ 11 ] and UC [ 12 , 13 , 14 ] colonic biopsies. In the animal model used in the current and other studies [ 14 , 24 ], DSS treatment induces and recapitulates NET generation in the mouse colon. We further demonstrate that TNBS treatment also promotes NET formation in the inflamed mouse colon.…”

“…The administration of a pan-peptidyl arginine deiminase (PAD) inhibitor Cl-amidine [ 46 ] or streptonigrin [ 14 ], a selective peptidyl arginine deiminase-4 (PAD4) inhibitor that blocks histone citrullination for NET formation, reduces the clinical symptoms of DSS-induced colitis. Moreover, circulating NETs induce the prothrombotic state of colitis [ 24 ]. Apart from these published findings, data presented in the current study further highlight the destructive effect of NETs on the intestinal permeability and barrier function in the pathogenesis of colitis and its behind mechanism.…”

Onion bulb extract can both reverse and prevent colitis in mice via inhibition of pro-inflammatory signaling molecules and neutrophil activity

“…High levels of neutrophil extracellular traps (NETs) were detected in the plasma and colon tissue of IBD patients with active disease state as well as in mice treated with DSS. Inhibition of NET release (through DNase administration) ameliorated colitis as well as colitis-associated tumorigenesis [ 58 ]. In addition, neutrophils are one of the major source of reactive oxygen species (ROS) which trigger tissue injury and lead to chronic inflammation and tumorigenesis [ 59 , 60 ].…”

Emodin alleviates LPS-induced inflammatory response in lung injury mice by affecting the function of neutrophils

“…However, other studies have also shown that a large number of extensive NETs formations can damage epithelial cells and endothelial cells [35] . Our research results show that the production of NETs is higher than that of the control group following LPS stimulation of neutrophils, which indicates that the production of NETs are helpful in enabling neutrophils to play a bactericidal function in the acute stages of inflammation.…”