Neutrophil Extracellular Trap-Driven Occlusive Diseases

Abstract

The enlightenment of the formation of neutrophil extracellular traps (NETs) as a part of the innate immune system shed new insights into the pathologies of various diseases. The initial idea that NETs are a pivotal defense structure was gradually amended due to several deleterious effects in consecutive investigations. NETs formation is now considered a double-edged sword. The harmful effects are not limited to the induction of inflammation by NETs remnants but also include occlusions caused by aggregated NETs (aggNETs). The latter carries the risk of occluding tubular structures like vessels or ducts and appear to be associated with the pathologies of various diseases. In addition to life-threatening vascular clogging, other occlusions include painful stone formation in the biliary system, the kidneys, the prostate, and the appendix. AggNETs are also prone to occlude the ductal system of exocrine glands, as seen in ocular glands, salivary glands, and others. Last, but not least, they also clog the pancreatic ducts in a murine model of neutrophilia. In this regard, elucidating the mechanism of NETs-dependent occlusions is of crucial importance for the development of new therapeutic approaches. Therefore, the purpose of this review is to address the putative mechanisms of NETs-associated occlusions in the pathogenesis of disease, as well as prospective treatment modalities.

Extracellular traps and the role in thrombosis

“…DNase degrades NETs by hydrolyzing the DNA backbone ( 11 ) and reduces the size and amount of aggNETs ( 173 ). Lack of dual host protector DNases in vivo cannot remove ETs efficiently, and aggETs can occlude vessels ( 21 ). The homeostatic balance between NET formation and degradation is dependent on adequate DNase activity ( 174 ).…”

“…There are three forms of ETs: aggregated ETs (aggETs), full-size ETs, and ET remnants. However, the main prothrombotic inducer remains debatable ( 21 ). Nevertheless, many important functions of these different types of ETs, such as NETs, macrophage/monocyte extracellular traps (METs), and mast cell extracellular traps (MCETs), remain incompletely understood.…”

Neutrophils’ Extracellular Trap Mechanisms: From Physiology to Pathology

“…The decondensed, extruded DNA is much more extended than the cell it is derived from and immobilizes and kills invaders while also acting as a physical barrier to inflammatory mediators [ 4 , 5 , 6 ]. NETs form not only in response to invaders but also in response to endogenous inflammatory signals [ 7 , 8 ]. While NETs beneficially eliminate invaders, neutrophils release a variety of pro-inflammatory mediators during their formation.…”

“…NET-driven inflammation is involved in several autoimmune diseases [ 7 , 9 ]. Indeed, if inflammatory NET-related signals persist for an extended period, aggregated NETs (aggNETs) can cause vascular and ductal occlusions [ 8 ]. The aim of this review is to present a general but detailed profile of NETs and their properties suitable for both scientists new to the field and for more experienced readers who wish to deepen their knowledge.…”

NET Formation in Systemic Lupus Erythematosus: Changes during the COVID-19 Pandemic

“…NETs are composed of a chromatin scaffold equipped with various granular and cytoplasmic neutrophilic enzymes necessary for the killing of pathogens and the degradation of pro-inflammatory cytokines and chemokines. However, an unbalance in NET formation is also implicated in many rheumatic and autoimmune diseases, and NETs reportedly occlude vessels and ducts [ 15 , 16 ]. This disbalance between NET formation and degradation is also increasingly acknowledged to play a major part in the pathophysiology of coagulopathy, inflammation, immune-mediated thrombotic events, and organ damage in patients with severe COVID-19 [ 17 ].…”