*For medical professionals only
Neutrophils are one of the most active and powerful immune cells.
After an infection, it is the first immune cells to rush from the bloodstream to the diseased tissue.
In the process of fighting pathogens, neutrophils are also very vicious, they can engulf pathogens, can release reactive oxygen species to kill pathogens, and even stop pathogens by their own death.
The phenomenon that neutrophils fight pathogens by "committing suicide" was first discovered by scientists in 2004 [1]. In simple terms, activated neutrophils release nuclear DNA into the cell when confronted with pathogenic microorganisms, where they capture and neutralize pathogens through neutrophil extracellular trapping nets (NETs) [2].
Schematic diagram of neutrophil extracellular trap net[2]
Now that the DNA has been released, the neutrophils must have died, and scientists call this programmed death of neutrophils NETosis [2]. Scientists have long believed that NETosis and apoptosis are two separate death processes.
However, a research team led by Ben A. Crocker of the University of California, San Diego, and Yangfang "Peipei" Zhu of Augusta University recently published an important research paper in the prestigious journal Science Advances [3], challenging our understanding of cell death.
Their study showed that neutrophil apoptosis and NETosis were not unrelated, but rather two successive death processes. In simple terms, apoptosis of neutrophils further triggers NETosis. It is understood that this is also the first time that scientists have found an association between apoptosis and NETosis.
Notably, after combining previous studies, the researchers found that in neutrophils, multiple pathways of death (pyroptosis, necrosis) converge on NETosis. Since neutrophil NET is associated with tumors and some autoimmune diseases, this discovery may lead to new therapeutic ideas.
Screenshot of the first page of the paper
Apoptosis must be no stranger to everyone. It is an important form of programmed death and is important for maintaining the stability of the body.
NETosis has been around for nearly 20 years since its discovery, and scientists already know how it happens. In simple terms, in neutrophils, the perforation proteins GSDMD (involved in pyroptosis) and MLKL (involved in cell necrosis) punch holes in the neutrophil membrane, resulting in an influx of calcium ions into the cell, followed by activation of peptidyl arginine deiminase 4 (PAD4), which in turn informs histone citrullination, a change that causes DNA to unwind from histones and then squeeze DNA out of the cell to form NETs that capture pathogens [4].
Two deaths of neutrophils
To explore the relationship between apoptosis and NETosis, Croker's team first stimulated neutrophils with a variety of apoptosis-inducing substances.
As a result, they found that histones were generally citrullinated, suggesting a possible link between apoptosis and NETosis. After knockout of PAD4 in neutrophils, histone citrullination disappears. The above studies show that apoptosis is indeed closely related to NETosis. They also confirmed these findings by staining the morphological changes of neutrophils.
As for the molecular mechanism behind it, the Coker team found that the apoptotic protease Caspases cleaves and activates the punching molecule GSDME, which leads to the influx of calcium ions into the cell, inducing NETosis. If the gene encoding GSDME is knocked out, neutrophils can also initiate apoptosis, but their ability to develop NETosis is greatly reduced.
Ben A. Convert (Yangfang "Baby" Zhu (2007)
Overall, the Crocker team's research shows that apoptosis and NETosis in neutrophils are not two separate processes. Neutrophils will gradually apoptosis after initiating the apoptosis signal, and if the apoptotic neutrophils are not eliminated in time, a second death program will be initiated.
Since apoptosis is a common programmed death pathway, and PAD enzymes are present in many types of cells, this finding could also be instructive for the study of other cell deaths. In addition, scientists have found that NETosis has been linked to some autoimmune diseases and tumors, so further exploration of the mechanisms behind it may help develop new therapies.
Bibliography:
[1]. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science. 2004; 303(5663):1532-1535. doi:10.1126/science.1092385
[2]. Thiam HR, Wong SL, Wagner DD, Waterman CM. Cellular Mechanisms of NETosis. Annu Rev Cell Dev Biol. 2020;36:191-218. doi:10.1146/annurev-cellbio-020520-111016
[3]. Zhu YP, Speir M, Tan Z, et al. NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils. Sci Adv. 2023; 9(51):eadj1397. doi:10.1126/sciadv.adj1397
[4]. Souza FW, Miao EA. Neutrophils only die twice. Sci Adv. 2023; 9(51):EADM8715. doi:10.1126/sciadv.adm8715
This article was written by BioTalker