Neutrophil Extracellular Trap Formation after Sterile Insults in Lung, Liver, Heart and Kidney: A Mini-Review

NET formation in noninfectious conditionsFormation of neutrophil extracellular traps (NETs), a new effector function of neutrophils, was first described in 2004 [1].Since then, the formation of NETs has widely been studied.NETs have a web-like structure mainly made of decondensed chromatin fibers, whose expulsion from the cell is aided by enzymatic citrullination of histones and which are decorated with granule proteins, such as elastase, myeloperoxidase (MPO) and histones [2,3].There is ample evidence supporting the idea that formation of NETs plays an important role in immune responses, allowing neutrophils to capture, neutralize, and degrade a variety of invading microorganisms.NETosis, the type of programmed cell death resulting in NET formation, also occurs during sterile inflammation resulting in thrombosis [4,5], autoimmunity [6], and NET-mediated cytotoxicity [7,8], and therefore can be harmful.DNA and damage-associated molecular patterns (DAMPs) embedded within NETs act as alarmins, augmenting inflammation, and exerting cytotoxic effects.The prothrombotic role of NETs has been well documented [9][10][11].This feature of NETs may become problematic, especially in cases of sterile insults.Thus, while NETs may provide evolutionary advantages of trapping and killing bacteria in infectious diseases, they appear to do more harm in sterile inflammation and thrombosis, as dysregulated NET formation leads to vascular inflammation, thrombosis, and atherogenesis, Let us provide some examples of sterile insults causing NET formation.As shown by many of the studies we discuss below, ischemia/reperfusion (IR) injury is a clinically relevant cause for NET formation.IR injury is a major sterile insult resulting from hemoragic, traumatic or septic shock, burns, and surgical procedures, including organ transplantation.The response to IR injury is comprised of a diverse network ranging from, innate to adaptive immune responses.[12].Restoration of the blood supply, paradoxically, causes cell damage and exacerbation of inflammatory responses through reactive oxygen species (ROS) and other reactive molecules, worsening organ injury [13].However, the specific pathways that link IR to NETs are only partially understood.Besides IR injury, several milder insults are known to induce NET formation.Beiter et al. showed that NET formation increases in response to exhaustive treadmill or cycling exercise in healthy individuals [14].This study proved that NETosis is the main cause for increased cell-free DNA in the circulation, as reported in an earlier study [e.g., 15].Jain and coworkers analyzed NETosis associated with dry eye disease, in which hyperosmolar stress is considered the main factor [16].They further showed that hyperosmotic stress promotes NET formation by neutrophils [17].NETs have been found in venous and arterial thrombosis, trauma-induced coagulopathy, and disseminated intravascular coagulation [18][19][20].NETs promote clot formation; in addition to the interaction of NET components with the coagulation pathway, NETs provide scaffolds for clot growth by catching platelets, fibrin, von Willebrand factor (vWF), and other cells/molecules [21].It is notable that fluid shear stress is a critical factor for rapid and intense NETosis [22].Intriguingly, in sterile occlusive clots, fibrin suppresses NET generation, and the absence of fibrin promotes NETs.Shear-induced NETosis is strongly inversely correlated with fibrin in sterile occlusive clots.