New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation

Abstract

Recent data suggest that NETosis plays a crucial role in the innate immune response and disturbs the homeostasis of the immune system. NETosis is a form of neutrophil-specific cell death characterized by the release of large web-like structures referred to as neutrophil extracellular traps (NETs). NETs are composed of DNA strands associated with histones and decorated with about 20 different proteins, including neutrophil elastase, myeloperoxidase, cathepsin G, proteinase 3, high mobility group protein B1, and LL37. Reportedly, NETosis can be induced by several microbes, and particulate matter including sterile stimuli, via distinct cellular mechanisms. Meanwhile, suicidal NETosis and vital NETosis are controversial. As we enter the second decade of research on NETosis, we have partly understood NETs as double-edged swords of innate immunity. In this review, we will discuss the mechanisms of NETosis, its antimicrobial action, and role in autoimmune diseases, as well as the relatively new field of NET-associated mitochondrial DNA.

Keywords: NETosis; NETs; antimicrobial activity; autoimmune diseases; mitochondrial DNA.

Figure 1

(I) Several stimuli (e.g., bacteria, viruses, fungi) initiate NETosis by binding to neutrophil receptors (e.g., Fc receptors, TLRs), which activate the endoplasmic reticulum to release stored calcium ions. (II) Elevated cytoplasmic calcium levels increase PKC activity, which induces NADPH oxidase to assemble into a functional complex (PHOX). (III) Subsequently, PHOX (or alternatively the mitochondrial respiratory chain) generate ROS. (IV) ROS generation leads to the rupture of granules and the nuclear envelope. (V) Meanwhile, NE and MPO translocate to the nucleus. (VI) As a result, histone deimination and chromatin decondensation contribute to the formation of NETs. (VII) Finally, the rupture of the plasma membrane causes neutrophil lysis and allows the release of NETs.

Figure 2

Some NETosis-inducing stimuli involve TLR4 on platelets. Under these conditions, neutrophils release NETs via blebbing of the nuclear envelope and vesicular exportation. As a result, neutrophils become nuclear cytoplasts, which are still able to migrate and retain several conventional functions of viable neutrophil.