Molecular mechanisms and therapeutic target of NETosis in diseases

Abstract

Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web‐like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: “suicidal” NETosis and “vital” NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell‐free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small‐vessel vasculitis, inflammatory bowel disease, cancer, COVID‐19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll‐like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis‐induced diseases, and NETosis‐targeted therapy.

Zinc in Human Health and Infectious Diseases

“…Alternatively, PMNs kill pathogens by releasing neutrophil extracellular traps (NETs), which are abolished during zinc deficiency [ 218 ]. NETs are web-like structures composed of DNA, chromatin, fibers, and various neutrophil granule proteins [ 225 ]. NETosis is a double-edged sword for the immune system.…”

“…On the one hand, it is known that NETs can encapsulate, capture, and kill pathogens efficiently, especially large microorganisms such as C. albicans and Mycobacteria aggregates that are difficult to phagocytose. On the other hand, the excessive release of NETs can trigger and amplify inflammatory diseases such as sepsis, rheumatoid arthritis, or inflammatory bowel disease [ 225 ]. However, NETosis is an indispensable method to protect humans of invading harmful pathogens.…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…Some researchers have identified another type of NETosis: mitochondria-specific vital NETosis, in which the DNA core of NETs includes DNA of mitochondrial origin [ 150 ]. A detailed up-to-date summary can be found in the review by Huang et al [ 151 ].…”

Novel Peptidylarginine Deiminase Type 4 (PAD4) Inhibitors

“…The following table shows representative compounds tested for PAD4 inhibition and the biological data obtained from testing representative examples. …”