The emerging role of neutrophilic extracellular traps in intestinal disease

Abstract

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.

Pathophysiology of Inflammatory Bowel Disease: Innate Immune System

“…Some studies have described the participation of NETs in IBD as a double-edged sword. On the one hand, NETs can impede the spread of microorganisms by trapping them in an environment of microbicidal components, while also stimulating the healing of the intestinal mucosa upon injury and helping to sustain the stability of the intestinal epithelium [ 36 , 37 ]. On the other hand, increased neutrophil activity and exacerbated NETs production can impair intestinal mucosal barrier function, damage the intestinal epithelium, and accentuate disease symptoms [ 38 ].…”

The role of neutrophil extracellular traps in necrotizing enterocolitis

“…Neutrophils are the most abundant immune cells and first-line responders of the innate immune system ( 22 , 23 ). As polymorphonuclear cells, neutrophils are very motile, which enables them to migrate from peripheral vasculature into the tissue of recruitment ( 23 , 24 ).…”

“…Neutrophils are the most abundant immune cells and first-line responders of the innate immune system ( 22 , 23 ). As polymorphonuclear cells, neutrophils are very motile, which enables them to migrate from peripheral vasculature into the tissue of recruitment ( 23 , 24 ). One of the key functions in NEC pathogenesis is the activation of intestinal epithelial cell toll-like receptor 4 (TLR4) which leads to accelerated apoptosis of enterocytes and reduced rate of healing through impaired intestinal restoration and proliferation.…”

“…NETs are normally cleared by plasma DNAse 1 followed by removal by macrophages. Inappropriate or delayed clearance of NETs or NET components specifically the associated histones and proteases contribute to pathological conditions like sepsis ( 39 ), thrombosis ( 40 ), transfusion-associated acute lung injury ( 41 ), cancer development and metastasis ( 42 ), autoimmune diseases ( 23 , 43 ), and impaired wound healing ( 44 ) - mostly through induction of INF, proinflammatory cytokines, and the NLRP3 inflammasome ( 45 ). A major mechanism for the cytotoxic properties of histones in NETs is through direct binding to the plasma membrane causing calcium influx and loss of membrane barrier function ( 46 – 48 ).…”

Advances in research on the effectiveness and mechanism of Traditional Chinese Medicine formulas for colitis-associated colorectal cancer

“…PAD4 is activated in neutrophils and can mediate the formation of neutrophil extracellular traps (NETs) (Hawez et al, 2019). Recent studies indicate that the formation of NETs in IBD increases significantly (Mortensen et al, 2022) and is associated to the occurrence of CRC (Chen et al, 2022). NETs markers decreased after HQD treatment.…”