Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology

Abstract

Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation.

NETosis: Molecular Mechanisms, Role in Physiology and Pathology

“…The Ca 2+ -dependent generation of mtROS could serve as a predominant source of ROS in the case of NETosis induction by Ca 2+ ionophores (A23187 or ionomycin) [ 32 ] and some other stimuli [ 33 , 34 ]. These observations promote the concept of two different mechanisms of NETosis, one of which is independent of NADPH oxidase (see, the review [ 5 ]). However, mtROS can contribute to the initiation of NETosis due to stimulation of NADPH oxidase.…”

“…Apparently, combination of all these factors is necessary for activation of PAD4. Along with citrullination, histones can also undergo acetylation during NETosis, but its role in this process is still poorly understood [ 5 ]. Chromatin decondensation, as well as proteolytic damage of the nuclear lamina leads to the destruction of the nuclear envelope, and release of chromatin into the cytoplasm.…”

Oleic acid-based nanosystems for mitigating acute respiratory distress syndrome in mice through neutrophil suppression: how the particulate size affects therapeutic efficiency

“…Further investigation is necessary to elucidate the detailed mechanisms related to nanoparticle-induced NETosis. It is generally recognized that NETosis is a unique type of neutrophil death via the NADPH-oxidase (Nox)-dependent pathway [40]. Previous evidence [41] expressed that OA only induces Nox-dependent NETosis in human neutrophils.…”

Trypanosoma brucei brucei Induces Polymorphonuclear Neutrophil Activation and Neutrophil Extracellular Traps Release

“…NETs-related enzymes, such as neutrophil elastase (NE) and myeloperoxidase (MPO), translocate to the nucleus and fuse with chromatin (19). Finally, PMN membrane disintegration is mediated either by enhanced ROS production (20) or by actions of lytic proteins, such as gasdermin-D, mediating membrane pore formation and subsequent NETs extrusion into the extracellular matrix (21). NETs release is a regulated molecular process which depends on energy metabolism (22,23), activation of NOX and generation of ROS and Ca ++ -influx as second messengers among others (9).…”